Publications

2017

1. Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability
Julian MC, Li L, Garde S, Wilen R, and Tessier PM, Scientific Reports ,7 ,45259 (2017)
The ability of antibodies to accumulate affinity-enhancing mutations in their complementarity-determining regions (CDRs) without compromising thermodynamic stability is critical to their natural function. However, it is unclear if affinity mutations in the hypervariable CDRs generally impact antibody stability and to what extent additional compensatory mutations are required to maintain stability during affinity maturation. Here we have experimentally and computationally evaluated the functional contributions of mutations acquired by a human variable (VH) domain that was evolved using strong selections for enhanced stability and affinity for the Alzheimer’s Aβ42 peptide. Interestingly, half of the key affinity mutations in the CDRs were destabilizing. Moreover, the destabilizing effects of these mutations were compensated for by a subset of the affinity mutations that were also stabilizing. Our findings demonstrate that the accumulation of both affinity and stability mutations is necessary to maintain thermodynamic stability during extensive mutagenesis and affinity maturation in vitro, which is similar to findings for natural antibodies that are subjected to somatic hypermutation in vivo. These findings for diverse antibodies and antibody fragments specific for unrelated antigens suggest that the formation of the antigen-binding site is generally a destabilizing process and that co-enrichment for compensatory mutations is critical for maintaining thermodynamic stability.
@article{julian2017efficient,
title   = {Efficient affinity maturation of antibody variable domains requires co-selection of compensatory mutations to maintain thermodynamic stability},
author  = {Julian, Mark C and Li, Lijuan and Garde, Shekhar and Wilen, Rebecca and Tessier, Peter M},
journal = {Scientific Reports},
volume  = {7},
year    = {2017},
doi     = {10.1038/srep45259}
}

2. Effect of Guanidine and Arginine on Protein–Ligand Interactions in Multimodal Cation-Exchange Chromatography
Parimal S, Garde S, Cramer SM, Biotechnol Prog (in press) (2017)
The addition of fluid phase modifiers provides significant opportunities for increasing the selectivity of multimodal chromatography. In order to optimize this selectivity, it is important to understand the fundamental interactions between proteins and these modifiers. To this end, molecular dynamics (MD) simulations were first performed to study the interactions of guanidine and arginine with three proteins. The simulation results showed that both guanidine and arginine interacted primarily with the negatively charged regions on the proteins and that these regions could be readily predicted using electrostatic potential maps. Protein surface characterization was then carried out using computationally efficient coarse-grained techniques for a broader set of proteins which exhibited interesting chromatographic retention behavior upon the addition of these modifiers. It was shown that proteins exhibiting an increased retention in the presence of guanidine possessed hydrophobic regions adjacent to negatively charged regions on their surfaces. In contrast, proteins which exhibited a decreased binding in the presence of guanidine did not have hydrophobic regions adjacent to negatively charged patches. These results indicated that the effect of guanidine could be described as a combination of competitive binding, charge neutralization and increased hydrophobic interactions for certain proteins. In contrast, arginine resulted in a significant decrease in protein retention times primarily due to competition for the resin and steric effects, with minimal accompanying increase in hydrophobic interactions. The approach presented in this paper which employs MD simulations to guide the application of coarse-grained approaches is expected to be extremely useful for methods development in downstream bioprocesses.
@article{parimal2017effect,
title   = {Effect of guanidine and arginine on protein--ligand interactions in multimodal cation-exchange chromatography},
author  = {Parimal, Siddharth and Garde, Shekhar and Cramer, Steven M},
journal = {Biotechnology Progress},
year    = {2017},
doi     = {10.1002/btpr.2419}
}


2016

1. Understanding n-Octane Behavior near Graphene with Scaled Solvent-Solute Attractions
Wu E and Garde S, J. Phys. Chem. B ,120 (8) ,2033-2042 (2016)
We employ molecular dynamics simulations of n-octane near a layered graphene surface to study the related phenomena of solvation, density fluctuations, wettability, and structure and dynamics of n-octane molecules in the inhomogeneous interfacial environment. That solvation in bulk n-octane displays a lengthscale-dependent crossover similar to that of hydrophobic solvation in water is known. Here we show that, near an extended graphene interface having attractive interactions with n-octane, lengthscale-dependent solvation is similar to that in the bulk and displays a small to large crossover. However, as the n-octane–graphene interactions are reduced to make the surface increasingly solvophobic, the crossover behavior is modulated and essentially absent near the most solvophobic surfaces, similar to that in water near hydrophobic interfaces. We show that the macroscopic measure of wettability, namely, the contact angle, characterizes n-octane–graphene coupling over a limited range of attractions. In contrast, molecular measures such as the free energy of cavity formation or the local compressibility in the interfacial region provide an effective measure of this coupling over a broader range of attractions. Finally, as n-octane–graphene attractions are increased, the n-octane liquid displays a wetting transition and corresponding change from sigmoidal to layered density profile. Analysis of the local structure shows that n-octane molecules prefer approximately linear conformations and surface-parallel orientations near the graphene surface, and their translational dynamics slow down with increasing n-octane–graphene attractions. Our study highlights molecular scale behavior of n-octane molecules that is relevant to understanding nanoparticle–solvent coupling in composite materials with enhanced mechanical or thermal properties.
@article{wu2016understanding,
title   = {Understanding n-Octant Behavior near Graphene with Scaled Solvent-Solute Attractions},
author  = {Wu, Eugene and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {120},
number  = {8},
pages   = {2033--2042},
year    = {2016},
doi     = {10.1021/acs.jpcb.5b10262}
}


2015

1. Pathways to dewetting in hydrophobic confinement
Remsing RC, Xi E, Vembanur S, Sharma S, Debenedetti PG, Garde S, and Patel AJ, Proc. Natl. Acad. Sci. USA ,112 (27) ,8181-8186 (2015)
Liquid water can become metastable with respect to its vapor in hydrophobic confinement. The resulting dewetting transitions are often impeded by large kinetic barriers. According to macroscopic theory, such barriers arise from the free energy required to nucleate a critical vapor tube that spans the region between two hydrophobic surfaces-tubes with smaller radii collapse, whereas larger ones grow to dry the entire confined region. Using extensive molecular simulations of water between two nanoscopic hydrophobic surfaces, in conjunction with advanced sampling techniques, here we show that for intersurface separations that thermodynamically favor dewetting, the barrier to dewetting does not correspond to the formation of a (classical) critical vapor tube. Instead, it corresponds to an abrupt transition from an isolated cavity adjacent to one of the confining surfaces to a gap-spanning vapor tube that is already larger than the critical vapor tube anticipated by macroscopic theory. Correspondingly, the barrier to dewetting is also smaller than the classical expectation. We show that the peculiar nature of water density fluctuations adjacent to extended hydrophobic surfaces-namely, the enhanced likelihood of observing low-density fluctuations relative to Gaussian statistics—facilitates this nonclassical behavior. By stabilizing isolated cavities relative to vapor tubes, enhanced water density fluctuations thus stabilize novel pathways, which circumvent the classical barriers and offer diminished resistance to dewetting. Our results thus suggest a key role for fluctuations in speeding up the kinetics of numerous phenomena ranging from Cassie-Wenzel transitions on superhydrophobic surfaces, to hydrophobically driven biomolecular folding and assembly.
@article{remsing2015pathways,
title   = {Pathways to dewetting in hydrophobic confinement},
author  = {Remsing, Richard C. and Xi, Erte and Vembanur, Srivathsan and Sharma, Sumit and Debenedetti, Pablo G. and Garde, Shekhar and Patel, Amish J.},
journal = {Proc. Natl. Acad. Sci. USA},
volume  = {112},
number  = {27},
pages   = {8181--8186},
year    = {2015},
doi     = {10.1073/pnas.1503302112}
}

2. Lengthscale-Dependent Solvation and Density Fluctuations in n-Octane
Wu E and Garde S, J. Phys. Chem. B ,119 (29) ,9287-9294 (2015)
Much attention has been focused on the solvation and density fluctuations in water over the past decade. These studies have brought to light interesting physical features of solvation in condensed media, especially the dependence of solvation on the solute lengthscale, which may be general to many fluids. Here, we focus on the lengthscale-dependent solvation and density fluctuations in n-octane, a simple organic liquid. Using extensive molecular simulations, we show a crossover in the solvation of solvophobic solutes with increasing size in n-octane, with the specifics of the crossover depending on the shape of the solute. Large lengthscale solvation, which is dominated by interface formation, emerges over subnanoscopic lengthscales. The crossover in n-octane occurs at smaller lengthscales than that in water. We connect the lengthscale of crossover to the range of attractive interactions in the fluid. The onset of the crossover is accompanied by the emergence of non-Gaussian tails in density fluctuations in solute shaped observation volumes. Simulations over a range of temperatures highlight a corresponding thermodynamic crossover in solvation. Qualitative similarities between lengthscale-dependent solvation in water, n-octane, and Lennard-Jones fluids highlight the generality of the underlying physics of solvation.
@article{wu2015lengthscale,
title   = {Lengthscale-Dependent Solvation and Density Fluctuations in
n-Octane},
author  = {Wu, Eugene and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {119},
number  = {29},
pages   = {9287--9294},
year    = {2015},
doi     = {10.1021/jp509912v}
}

3. Interactions of Multimodal Ligands with Proteins: Insights into Selectivity Using Molecular Dynamics Simulations
Parimal S, Garde S, Cramer SM, Langmuir ,31 (27) ,7512-7523 (2015)
Fundamental understanding of protein–ligand interactions is important to the development of efficient bioseparations in multimodal chromatography. Here we employ molecular dynamics (MD) simulations to investigate the interactions of three different proteins—ubiquitin, cytochrome C, and α-chymotrypsinogen A, sampling a range of charge from +1e to +9e—with two multimodal chromatographic ligands containing similar chemical moieties—aromatic, carboxyl, and amide—in different structural arrangements. We use a spherical harmonic expansion to analyze ligand and individual moiety density profiles around the proteins. We find that the Capto MMC ligand, which contains an additional aliphatic group, displays stronger interactions than Nuvia CPrime ligand with all three proteins. Studying the ligand densities at the moiety level suggests that hydrophobic interactions play a major role in determining the locations of high ligand densities. Finally, the greater structural flexibility of the Capto MMC ligand compared to that of the Nuvia cPrime ligand allows for stronger structural complementarity and enables stronger hydrophobic interactions. These subtle and not-so-subtle differences in binding affinities and modalities for multimodal ligands can result in significantly different binding behavior towards proteins with important implications for bioprocessing.
@article{parimal2015interactions,
title   = {Interactions of Multimodal Ligands with Proteins: Insights
into Selectivity Using Molecular Dynamics Simulations},
author  = {Parimal, Siddharth and Garde, Shekhar and Cramer, Steven M},
journal = {Langmuir},
volume  = {31},
number  = {27},
pages   = {7512--7523},
year    = {2015},
doi     = {10.1021/acs.langmuir.5b00236}
}

4. Physical chemistry: Hydrophobic interactions in context
Garde S, Nature ,517 ,277-279 (2015)
The finding that immobilized ions can alter the strength of hydrophobic interactions between molecules suggests a strategy for tuning hydrophobicity to optimize molecular recognition and self-assembly processes.
@article{garde2015physical,
title   = {Physical chemistry: Hydrophobic interactions in context},
author  = {Garde, Shekhar},
journal = {Nature},
volume  = {517},
pages   = {277--279},
year    = {2015},
doi     = {10.1038/517277a}
}

5. Role of Arginine in Mediating Protein-Carbon Nanotube Interactions
Wu E, Coppens M-O and Garde S, Langmuir ,31 (5) ,1683-1692 (2015)
Arginine-rich proteins (e.g., lysozyme) or poly-l-arginine peptides have been suggested as solvating and dispersing agents for single-wall carbon nanotubes (CNTs) in water. In addition, protein structure–function in porous and hydrophobic materials is of broad interest. The amino acid residue, arginine (Arg+), has been implicated as an important mediator of protein/peptide–CNT interactions. To understand the structural and thermodynamic aspects of this interaction at the molecular level, we employ molecular dynamics (MD) simulations of the protein lysozyme in the interior of a CNT, as well as of free solutions of Arg+ in the presence of a CNT. To dissect the Arg+–CNT interaction further, we also perform simulations of aqueous solutions of the guanidinium ion (Gdm+) and the norvaline (Nva) residue in the presence of a CNT. We show that the interactions of lysozyme with the CNT are mediated by the surface Arg+ residues. The strong interaction of Arg+ residue with the CNT is primarily driven by the favorable interactions of the Gdm+ group with the CNT wall. The Gdm+ group is not as well-hydrated on its flat sides, which binds to the CNT wall. This is consistent with a similar binding of Gdm+ ions to a hydrophobic polymer. In contrast, the Nva residue, which lacks the Gdm+ group, binds to the CNT weakly. We present details of the free energy of binding, molecular structure, and dynamics of these solutes on the CNT surface. Our results highlight the important role of Arg+ residues in protein–CNT or protein-carbon-based material interactions. Such interactions could be manipulated precisely through protein engineering, thereby offering control over protein orientation and structure on CNTs, graphene, or other hydrophobic interfaces.
@article{wu2015role,
title   = {Role of Arginine in Mediating Protein–Carbon Nanotube
Interactions},
author  = {Wu, Eugene and Coppens, Marc-Olivier and Garde, Shekhar},
journal = {Langmuir},
volume  = {31},
number  = {5},
pages   = {1683--1692},
year    = {2015},
doi     = {10.1021/la5043553}
}


2014

1. Water at Functional Interfaces
Garde S and Schlossman ML, MRS Bulletin ,39 (12) ,1051-1053 (2014)
Water is, perhaps, the most important material known to humankind—fascinating even in its pure state for the range of anomalous properties it displays. There has been an increasing realization that understanding the behavior of water at interfaces—from those of small solutes to biomolecules and polymers to inorganic materials and metals—holds the key to understanding disparate phenomena, from self-assembly, biofouling, and catalysis to corrosion. In this issue of MRS Bulletin, we highlight recent advances in understanding the molecular behavior of water near a range of interfaces of interest to the broader materials community.
@article{garde2014water,
title   = {Water at functional interfaces},
author  = {Garde, Shekhar and Schlossman, Mark L},
journal = {MRS Bulletin},
volume  = {39},
number  = {12},
pages   = {1051--1053},
year    = {2014},
doi     = {10.1557/mrs.2014.280}
}

2. Binding, structure, and dynamics of hydrophobic polymers near patterned self-assembled monolayer surfaces
Li L and Garde S, Langmuir ,30 (47) ,14204-14211 (2014)
We use molecular dynamics simulations to study the binding, conformations, and dynamics of a flexible 25-mer hydrophobic polymer near well-defined patterned self-assembled monolayers containing a hydrophobic strip (with −CH3 head-groups) having different widths in a hydrophilic (−OH) background. We show that the polymer binds favorably to hydrophobic strips of all widths, including the subnanometer ones comprising 3, 2, or even 1 row of −CH3 head-groups, with the binding strength varying from about 107 to 25 kJ/mol for the widest to the narrowest strip. Near wide hydrophobic patches containing 5 or more −CH3 rows, pancakelike conformations are dominant, whereas hairpinlike structures become preferred ones near the narrower strips. In the vicinity of the narrowest 1-row strip, the polymer folds into semiglobular conformations, thus maintaining sufficient contact with the strip while sequestering its hydrophobic groups away from water. We also show that the confinement makes the translational dynamics of the polymer anisotropic as well as conformational dependent. Our results may help to understand and manipulate the self-assembly and dynamics of soft matter, such as polymers, peptides, and proteins, at inhomogeneous patterned surfaces.
@article{li2014binding,
title   = {Binding, Structure, and Dynamics of Hydrophobic
Polymers near Patterned Self-Assembled Monolayer Surfaces},
author  = {Li, Lijuan and Garde, Shekhar},
journal = {Langmuir},
volume  = {30},
number  = {47},
pages   = {14204--14211},
year    = {2014},
doi     = {10.1021/la503537b}
}

3. Application of a Spherical Harmonics Expansion Approach for Calculating Ligand Density Distributions around Proteins
Parimal S, Cramer SM and Garde S, J. Phys. Chem. B ,118 (46) ,13066-13076 (2014)
Protein–ligand interactions are central to many biological applications, including molecular recognition, protein formulations, and bioseparations. Complex, multisite ligands can have affinities for different locations on a protein’s surface, depending on the chemical and topographical complementarity. We employ an approach based on the spherical harmonic expansion to calculate spatially resolved three-dimensional atomic density profiles of water and ligands in the vicinity of macromolecules. To illustrate the approach, we first study the hydration of model C180 buckyball solutes, with nonspherical patterns of hydrophobicity/-philicity on their surface. We extend the approach to calculate density profiles of increasingly complex ligands and their constituent groups around a protein (ubiquitin) in aqueous solution. Analysis of density profiles provides information about the binding face of the protein and the preferred orientations of ligands on the binding surface. Our results highlight that the spherical harmonic expansion based approach is easy to implement and efficient for calculation and visualization of three-dimensional density profiles around spherically nonsymmetric and topographically and chemically complex solutes.
@article{Parimal2014application,
title   = {Application of a Spherical Harmonics Expansion Approach
for Calculating Ligand Density Distributions around Proteins},
author  = {Parimal, Siddharth and Cramer, Steven M and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {118},
number  = {46},
year    = {2014},
pages   = {13066-13076},
doi     = {10.1021/jp506849k}
}

4. Connecting water correlations, fluctuations, and wetting phenomena at hydrophobic and hydrophilic surfaces
Godawat R, Jamadagni SN, Venkateshwaran V and Garde S, arXiv preprint (2014)
We use molecular simulations to demonstrate the connection between transverse water-water correlations and wetting phenomena for a range of hydrophobic to hydrophilic solid surfaces.Near superhydrophobic surfaces, the correlations are long ranged, system spanning, and are well described by the capillary wave theory. With increasing surface-water attractions, the correlations are quenched. At the critical attraction at which long range correlations disappear, the density profile normal to the surface changes from sigmoidal to layered, and the fluid begins to wet the surface. This behavior is displayed by both water and a Lennard-Jones fluid, highlighting the universality of the underlying physics.

5. Water-mediated ion-ion interactions are enhanced at the water vapor-liquid interface
Venkateshwaran V, Vembanur S and Garde S, Proc. Natl. Acad. Sci. USA ,111 (24) ,8729-8734 (2014)
There is overwhelming evidence that ions are present near the vapor–liquid interface of aqueous salt solutions. Charged groups can also be driven to interfaces by attaching them to hydrophobic moieties. Despite their importance in many self-assembly phenom- ena, how ion–ion interactions are affected by interfaces is not understood. We use molecular simulations to show that the effec- tive forces between small ions change character dramatically near the water vapor–liquid interface. Specifically, the water-mediated attraction between oppositely charged ions is enhanced relative to that in bulk water. Further, the repulsion between like-charged ions is weaker than that expected from a continuum dielectric description and can even become attractive as the ions are drawn to the vapor side. We show that thermodynamics of ion associa- tion are governed by a delicate balance of ion hydration, in- terfacial tension, and restriction of capillary fluctuations at the interface, leading to nonintuitive phenomena, such as water- mediated like charge attraction. “Sticky” electrostatic interactions may have important consequences on biomolecular structure, as- sembly, and aggregation at soft liquid interfaces. We demonstrate this by studying an interfacially active model peptide that changes its structure from α-helical to a hairpin-turn–like one in response to charging of its ends.
@article{venkateshwaran2014water,
title   = {Water-mediated ion-ion interactions are enhanced at the water vapor-liquid interface},
author  = {Venkateshwaran, Vasudevan and Vembanur, Srivathsan and Garde, Shekhar},
journal = {Proc. Natl. Acad. Sci. USA},
volume  = {111},
number  = {24},
pages   = {8729-8734},
year    = {2014},
doi     = {10.1073/pnas.1403294111}
}

6. Structure and dynamics of single hydrophobic/ionic heteropolymers at the vapor-liquid interface of water
Vembanur S, Venkateshwaran V and Garde S, Langmuir ,30 (16) ,4654-4661 (2014)
We focus on the conformational stability, structure, and dynamics of hydrophobic/charged homo- and heteropolymers at a vapor-liquid interface of water using extensive molecular dynamics simulations. Hydrophobic polymers collapse into globular structures in bulk water, but unfold and sample a broad range of conformations at the vapor-liquid interface of water. We show that adding a pair of charges to a hydrophobic polymer at the interface can dramatically change its conformations, stabilizing hairpin-like structures, with molecular details depending on the location of the charged pair in the sequence. The translational dynamics of homo- and heteropolymers are also different -- whereas the homopolymers skate on the interface with low drag, the tendency of charged groups to remain hydrated pulls the heteropolymers toward the liquid side of the interface, thus pinning them, increasing drag, and slowing the translational dynamics. The conformational dynamics of heteropolymers are also slower than that of the homopolymer, and depend on the location of the charged groups in the sequence. Conformational dynamics are most restricted for the end-charged heteropolymer, and speed up as the charge pair is moved toward the center of the sequence. We rationalize these trends using the fundamental understanding of the effects of the interface on primitive pair-level interactions between two hydrophobic groups or between oppositely charged ions in its vicinity.
@article{vembanur2014structure,
title   = {Structure and dynamics of single hydrophobic/ionic heteropolymers at the vapor-liquid interface of water},
author  = {Vembanur, Srivathsan and Venkateshwaran, Vasudevan and Garde, Shekhar},
journal = {Langmuir},
volume  = {30},
number  = {16},
pages   = {4654-4661},
year    = {2014},
doi     = {10.1021/la500237u}
}

7. Efficient Method To Characterize the Context-Dependent Hydrophobicity of Proteins
Patel AJ and Garde S, J. Phys. Chem. B ,118 (6) ,1564-1573 (2014)
Characterizing the hydrophobicity of a protein surface is relevant to understanding and quantifying its interactions with ligands, other proteins, and extended interfaces. However, the hydrophobicity of a complex, heterogeneous protein surface depends not only on the chemistry of the underlying amino acids but also on the precise chemical pattern and topographical context presented by the surface. Characterization of such context-dependent hydrophobicity at nanoscale resolution is a nontrivial task. The free energy, μvex, of forming a cavity near a surface has been shown to be a robust measure of context-dependent hydrophobicity, with more favorable μvex values suggesting hydrophobic regions. However, estimating μvex for cavities significantly larger than the size of a methane molecule in a spatially resolved manner near proteins is a computationally daunting task. Here, we present a new method for estimating μvex that is 2 orders of magnitude more efficient than conventional techniques. Our method envisions cavity creation as the emptying of a volume of interest, v, by applying an external potential that is proportional to the number of water molecules, Nv, in v. We show that the “force” to be integrated to obtain μvex is simply the average of Nv in the presence of the potential, and can be sampled accurately using short simulations (50–100 ps), making our method very efficient. By leveraging the efficiency of the method to calculate μvex at various locations in the hydration shell of the protein, hydrophobin II, we are able to construct a hydrophobicity map of the protein that accounts for topographical and chemical context. Interestingly, we find that the map is also dependent on the shape and size of v, suggesting an “observer context” in mapping the hydrophobicity of protein surfaces.
@article{patel2014efficient,
title   = {Efficient Method To Characterize the Context-Dependent
Hydrophobicity of Proteins},
author  = {Patel, Amish J and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {118},
number  = {6},
pages   = {1564-1573},
year    = {2014},
doi     = {10.1021/jp4081977}
}


2013

1. On the Thermodynamics and Kinetics of Hydrophobic Interactions at Interfaces
Vembanur S, Patel AJ, Sarupria S and Garde S, J. Phys. Chem. B ,117 (35) ,10261--10270 (2013)
We have studied how primitive hydrophobic interactions between two or more small nonpolar solutes are affected by the presence of surfaces. We show that the desolvation barriers present in the potential of mean force between the solutes in bulk water are significantly reduced near an extended hydrophobic surface. Correspondingly, the kinetics of hydrophobic contact formation and breakage are faster near a hydrophobic surface than near a hydrophilic surface or in the bulk. We propose that the reduction in the desolvation barrier is a consequence of the fact that water near extended hydrophobic surfaces is akin to that at a liquid–vapor interface and is easily displaced. We support this proposal with three independent observations. First, when small hydrophobic solutes are brought near a hydrophobic surface, they induce local dewetting, thereby facilitating the reduction of desolvation barriers. Second, our results and those of Patel et al. ( Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 17678−17683) show that, whereas the association of small solutes in bulk water is driven by entropy, that near hydrophobic surfaces is driven by enthalpy, suggesting that the physics of interface deformation is important. Third, moving water away from its vapor–liquid coexistence, by applying hydrostatic pressure, leads to recovery of bulklike signatures (e.g., the presence of a desolvation barrier and an entropic driving force) in the association of solutes. These observations for simple solutes also translate to end-to-end contact formation in a model peptide with hydrophobic end groups, for which lowering of the desolvation barrier and acceleration of contact formation are observed near a hydrophobic surface. Our results suggest that extended hydrophobic surfaces, such as air–water or hydrocarbon–water surfaces, could serve as excellent platforms for catalyzing hydrophobically driven assembly.
@article{vembanur2013thermodynamics,
title   = {On the Thermodynamics and Kinetics of Hydrophobic
Interactions at Interfaces},
author  = {Vembanur, Srivathsan and Patel, Amish J and Sarupria, Sapna
and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {117},
number  = {35},
pages   = {10261--10270},
year    = {2013},
doi     = {10.1021/jp4050513}
}

2. Trimethylamine N-oxide (TMAO) and tertiary butyl alcohol (TBA) at hydrophobic interfaces: Insights from molecular dynamics simulations
Fiore A, Venkateshwaran V and Garde S, Langmuir ,29 (25) ,8017--8024 (2013)
TMAO, a potent osmolyte, and TBA, a denaturant, have similar molecular architecture but somewhat different chemistry. We employ extensive molecular dynamics simulations to quantify their behavior at vapor--water and octane--water interfaces. We show that interfacial structure, density and orientation and their dependence on solution concentration are markedly different for the two molecules. TMAO molecules are moderately surface active and adopt orientations with their N--O vector approximately parallel to the aqueous interface. That is, not all methyl groups of TMAO at the interface point away from the water phase. In contrast, TBA molecules act as molecular amphiphiles, are highly surface active, and, at low concentrations, adopt orientations with their methyl groups pointing away and the C--O vector pointing directly into water. The behavior of TMAO at aqueous interfaces is only weakly dependent on its solution concentration, whereas that of TBA depends strongly on concentration. We show that this concentration dependence arises from their different hydrogen bonding capabilities, TMAO can only accept hydrogen bonds from water, whereas TBA can accept (donate) hydrogen bonds from (to) water or other TBA molecules. The ability to self-associate, particularly visible in TBA molecules in the interfacial layer, allows them to sample a broad range of orientations at higher concentrations. In light of the role of TMAO and TBA in biomolecular stability, our results provide a reference with which to compare their behavior near biological interfaces. Also, given the ubiquity of aqueous interfaces in biology, chemistry, and technology, our results may be useful in the design of interfacially active small molecules with the aim to control their orientations and interactions.
@article{ fiore2013trimethylamine,
title   ={Trimethylamine N-oxide (TMAO) and tertiary butyl alcohol (TBA)
at hydrophobic interfaces: Insights from molecular dynamics
simulations},
author  = {Fiore, Andrew and Venkateshwaran, Vasudevan and Garde, Shekhar},
journal = {Langmuir},
year    = {2013},
volume  = {29},
number  = {25},
pages   = {8017--8024},
doi     = {10.1021/la401203r}
}


2012

1. Sitting at the Edge: How Biomolecules use Hydrophobicity to Tune Their Interactions and Function
Patel AJP, Varilly P, Jamadagni SN, Hagan MF, Chandler D, and Garde S, J. Phys. Chem. B ,116 (8) ,2498--2503 (2012)
Water near extended hydrophobic surfaces is like that at a liquid--vapor interface, where fluctuations in water density are substantially enhanced compared to those in bulk water. Here we use molecular simulations with specialized sampling techniques to show that water density fluctuations are similarly enhanced, even near hydrophobic surfaces of complex biomolecules, situating them at the edge of a dewetting transition. Consequently, water near these surfaces is sensitive to subtle changes in surface conformation, topology, and chemistry, any of which can tip the balance toward or away from the wet state and thus significantly alter biomolecular interactions and function. Our work also resolves the long-standing puzzle of why some biological surfaces dewet and other seemingly similar surfaces do not.
@article{ patel2012sitting,
title   = {Sitting at the Edge: How Biomolecules use Hydrophobicity to
Tune Their Interactions and Function},
author  = {Patel, Amish J. and Varilly, Patrick and Jamadagni, Sumanth N.
and Hagan, Michael F. and Chandler, David and Garde, Shekhar},
journal = {J. Phys. Chem. B},
year    = {2012},
volume  = {116},
number  = {8},
pages   = {2498--2503},
doi     = {10.1021/jp2107523}
}

2. How Chemistry, Nanoscale Roughness, and the Direction of Heat Flow Affect Thermal Conductance of Solid--Water Interfaces
Acharya H, Mozdzierz NJ, Keblinski P, and Garde S, Ind. Eng. Chem. Res. ,51 (4) ,1767--1773 (2012)
We quantify the Kapitza thermal conductance of solid--liquid interfaces between self-assembled monolayers (SAMs) and liquid water using nonequilibrium molecular dynamics simulations. We focus on understanding how surface chemistry, nanoscale roughness, and the direction of heat flow affect interfacial thermal conductance. In agreement with calculations by Shenogina et al. (Phys. Rev. Lett., 2009, 102, 156101) for SAMs with homogeneous headgroup chemistries, we find that for mixed --CF3/--OH SAMs, thermal conductance increases roughly linearly with the fraction of -OH groups on the surface. Increasing nanoscale roughness increases solid--water contact area, and therefore the apparent thermal conductance. However, the inherent thermal conductance, which accounts for the increased contact area, shows only small and subtle variations. These variations are consistent with expectations based on recent work on the effects of nanoscale roughness on interfacial tension (Mittal and Hummer, Faraday Disc., 2010, 146, 341). Finally, we find that SAM--water interfaces show thermal rectification. Thermal conductance is larger when heat flows from the ordered SAM phase to the disordered liquid water phase, and the magnitude of rectification increases with surface hydrophilicity.
@article{ acharya2012how,
author  = {Acharya, Hari and Mozdzierz, Nicholas J. and Keblinski, Pawel
and Garde, Shekhar},
title   = {How Chemistry, Nanoscale Roughness, and the Direction of Heat
Flow Affect Thermal Conductance of Solid--Water Interfaces},
journal = {Industrial & Engineering Chemistry Research},
volume = {51},
number = {4},
pages = {1767-1773},
year = {2012},
doi = {10.1021/ie2010274},
}


2011

1. Unraveling the hydrophobic effect, one molecule at a time
Garde S and Patel AJ, Proc. Natl. Acad. Sci. USA ,108 (40) ,16491-16492 (2011)
@article{Garde04102011,
author  = {Garde, Shekhar and Patel, Amish J.},
title   = {Unraveling the hydrophobic effect, one molecule at a time},
journal = {Proc. Natl. Acad. Sci. USA}
volume  = {108},
number  = {40},
pages   = {16491-16492},
year    = {2011},
doi     = {10.1073/pnas.1113256108},
}

2. Molecular Simulations of Multimodal Ligand--Protein Binding: Elucidation of Binding Sites and Correlation with Experiments
Freed AS, Garde S and Cramer SM, J. Phys. Chem. B ,115 (45) ,13320--13327 (2011)
Multimodal chromatography, which employs more than one mode of interaction between ligands and proteins, has been shown to have unique selectivity and high efficacy for protein purification. To test the ability of free solution molecular dynamics (MD) simulations in explicit water to identify binding regions on the protein surface and to shed light on the pseudo affinity nature of multimodal interactions, we performed MD simulations of a model protein ubiquitin in aqueous solution of free ligands. Comparisons of MD with NMR spectroscopy of ubiquitin mutants in solutions of free ligands show a good agreement between the two with regard to the preferred binding region on the surface of the protein and several binding sites. MD simulations also identify additional binding sites that were not observed in the NMR experiments. Bound ligands were found to be sufficiently flexible and to access a number of favorable conformations, suggesting only a moderate loss of ligand entropy in the pseudo affinity binding of these multimodal ligands. Analysis of locations of chemical subunits of the ligand on the protein surface indicated that electrostatic interaction units were located on the periphery of the preferred binding region on the protein. The analysis of the electrostatic potential, the hydrophobicity maps, and the binding of both acetate and benzene probes were used to further study the localization of individual ligand moieties. These results suggest that water-mediated electrostatic interactions help the localization and orientation of the MM ligand to the binding region with additional stability provided by nonspecific hydrophobic interactions.
@article{freed2011molecular,
title   = {Molecular simulations of multimodal ligand--protein binding:
Elucidation of binding sites and correlation with experiments},
author  = {Freed, Alexander S. and Garde, Shekhar and Cramer, Steven M.},
journal = {J. Phys. Chem. B},
volume  = {115},
number  = {45},
pages   = {13320--13327},
year    = {2011},
doi     = {10.1021/la401203r}
}

3. Extended surfaces modulate hydrophobic interactions of neighboring solutes
Patel AJ, Varilly P, Jamadagni SN, Acharya H, Garde S and Chandler D, Proc. Natl. Acad. Sci. USA ,108 (43) ,17678-17683 (2011)
Interfaces are a most common motif in complex systems. To understand how the presence of interfaces affects hydrophobic phenomena, we use molecular simulations and theory to study hydration of solutes at interfaces. The solutes range in size from subnanometer to a few nanometers. The interfaces are self-assembled monolayers with a range of chemistries, from hydrophilic to hydrophobic. We show that the driving force for assembly in the vicinity of a hydrophobic surface is weaker than that in bulk water and decreases with increasing temperature, in contrast to that in the bulk. We explain these distinct features in terms of an interplay between interfacial fluctuations and excluded volume effect, the physics encoded in Lum--Chandler--Weeks theory [Lum K, Chandler D, Weeks JD (1999) J Phys Chem B 103:4570--4577]. Our results suggest a catalytic role for hydrophobic interfaces in the unfolding of proteins, for example, in the interior of chaperonins and in amyloid formation.
@article{Patel25102011,
title   = {Extended surfaces modulate hydrophobic interactions of
neighboring solutes},
author  = {Patel, Amish J. and Varilly, Patrick and
Jamadagni, Sumanth N. and Acharya, Hari and
Garde, Shekhar and Chandler, David}
journal = {Proc. Natl. Acad. Sci. USA}
volume  = {108},
number  = {43},
pages   = {17678-17683},
year    = {2011},
doi     = {10.1073/pnas.1110703108},
}

4. Quantifying Density Fluctuations in Volumes of All Shapes and Sizes Using Indirect Umbrella Sampling
Patel AJ, Varilly P, Chandler D and Garde S, J. Stat. Phys. ,145 (2) ,265-275 (2011)
Water density fluctuations are an important statistical mechanical observable and are related to many-body correlations, as well as hydrophobic hydration and interactions. Local water density fluctuations at a solid-water surface have also been proposed as a measure of its hydrophobicity. These fluctuations can be quantified by calculating the probability, Pv(N), of observing N waters in a probe volume of interest v. When v is large, calculating Pv(N) using molecular dynamics simulations is challenging, as the probability of observing very few waters is exponentially small, and the standard procedure for overcoming this problem (umbrella sampling in N) leads to undesirable impulsive forces. Patel et al. (J. Phys. Chem. B 114:1632, 2010) have recently developed an indirect umbrella sampling (INDUS) method, that samples a coarse-grained particle number to obtain P v (N) in cuboidal volumes. Here, we present and demonstrate an extension of that approach to volumes of other basic shapes, like spheres and cylinders, as well as to collections of such volumes. We further describe the implementation of INDUS in the NPT ensemble and calculate Pv(N) distributions over a broad range of pressures. Our method may be of particular interest in characterizing the hydrophobicity of interfaces of proteins, nanotubes and related systems.
@article{Patel2011quantifying,
title   = {Quantifying Density Fluctuations in Volumes of All Shapes and
Sizes Using Indirect Umbrella Sampling},
author  = {Patel, Amish J. and Varilly, Patrick and Chandler, David and
Garde, Shekhar},
journal = {J. Stat. Phys.},
volume  = {145},
number  = {2},
year    = {2011},
pages   = {265-275},
doi     = {10.1007/s10955-011-0269-9},
}

5. Hydrophobicity of Proteins and Interfaces: Insights from Density Fluctuations
Jamadagni SN, Godawat R and Garde S, Annu. Rev. Chem. Biomol. Eng. ,2 ,147-171 (2011)
Macroscopic characterizations of hydrophobicity (e.g., contact angle measurements) do not extend to the surfaces of proteins and nanoparticles. Molecular measures of hydrophobicity of such surfaces need to account for the behavior of hydration water. Theory and state-of-the-art simulations suggest that water density fluctuations provide such a measure; fluctuations are enhanced near hydrophobic surfaces and quenched with increasing surface hydrophilicity. Fluctuations affect conformational equilibria and dynamics of molecules at interfaces. Enhanced fluctuations are reflected in enhanced cavity formation, more favorable binding of hydrophobic solutes, increased compressibility of hydration water, and enhanced water-water correlations at hydrophobic surfaces. These density fluctuation based measures can be used to develop practical methods to map the hydrophobicity/philicity of heterogeneous surfaces including those of proteins. They highlight that the hydrophobicity of a group is context dependent and is significantly affected by its environment (e.g., chemistry and topography) and especially by confinement. The ability to include information about hydration water in mapping hydrophobicity is expected to significantly impact our understanding of protein-protein interactions as well as improve drug design and discovery methods and bioseparation processes.
@article{
title   = {Hydrophobicity of Proteins and Interfaces: Insights from
Density Fluctuations},
author  = {Jamadagni, Sumanth N. and Godawat, Rahul and Garde, Shekhar},
journal = {Annual Review of Chemical and Biomolecular Engineering},
volume  = {2},
number  = {1},
pages   = {147-171},
year    = {2011},
doi     = {10.1146/annurev-chembioeng-061010-114156},
}


2010

1. Dedication of the issue to Prof. E. Bruce Nauman (1937-2009)
Garde S, Nigam A and Nigam KDP, Chemical Engineering and Processing ,49 ,633-634 (2010)

2. Lubrication by molecularly thin water films confined between nanostructured membranes
Kalra A, Garde S and Hummer G, Euro. Phys. J. - Special Topics ,189 ,147-154 (2010)
We use molecular dynamics simulations to study thermal sliding of two nanostructured surfaces separated by nanoscale water films. We find that friction at molecular separations is determined primarily by the effective free energy landscape for motion in the plane of sliding, which depends sensitively on the surface character and the molecular structure of the confined water. Small changes in the surface nanostructure can have dramatic effects on the apparent rheology. Whereas porous and molecularly rough interfaces of open carbon nanotube membranes are found to glide with little friction, a comparably smooth interface of end-capped nanotubes is effectively stuck. The addition of salt to the water layer is found to reduce the sliding friction. Surprisingly, the intervening layers of water remain fluid in all cases, even in the case of high apparent friction between the two membranes.
@article{kalra2010lubrication,
title   = {Lubrication by molecularly thin water films confined between
nanostructured membranes},
author  = {Kalra, A and Garde, S and Hummer, G},
journal = {The European Physical Journal Special Topics},
volume  = {189},
number  = {1},
pages   = {147--154},
year    = {2010},
doi     = {10.1140/epjst/e2010-01317-9}
}

3. Designing heteropolymers to fold into unique structures via water-mediated interactions
Jamadagni SN, Bosoy C and Garde S, J. Phys. Chem. B ,114 (42) ,13282-13288 (2010)
Hydrophobic homopolymers collapse into globular structures in water driven by hydrophobic interactions. Here we employ extensive molecular dynamics simulations to study the collapse of heteropolymers containing one or two pairs of oppositely charged monomers. We show that charging a pair of monomers can dramatically alter the most stable conformations from compact globular to more open hairpin-like. We systematically explore a subset of the sequence space of one- and two-charge-pair polymers, focusing on the locations of the charge pairs. Conformational stability is governed by a balance of hydrophobic interactions, hydration and interactions of charge groups, water-mediated charged-hydrophobic monomer repulsions, and other factors. As a result, placing charge pairs in the middle, away from the hairpin ends, leads to stable hairpin-like structures. Turning off the monomer−water attractions enhances hydrophobic interactions significantly leading to a collapse into compact globular structures even for two-charge-pair heteropolymers. In contrast, the addition of salt leads to open and extended structures, suggesting that solvation of charged monomer sites by salt ions dominates the salt-induced enhancement of hydrophobic interactions. We also test the ability of a predictive scheme based on the additivity of free energy of contact formation. The success of the scheme for symmetric two-charge-pair sequences and the failure for their flipped versions highlight the complexity of the heteropolymer conformation space and of the design problem. Collectively, our results underscore the ability of tuning water-mediated interactions to design stable nonglobular structures in water and present model heteropolymers for further studies in the extended thermodynamic space and in inhomogeneous environments.
@article{jamadagni2010designing,
title   = {Designing Heteropolymers To Fold into Unique Structures
via Water-Mediated Interactions},
author  = {Jamadagni, Sumanth N and Bosoy, Christian and Garde, Shekhar},
journal = {The Journal of Physical Chemistry B},
volume  = {114},
number  = {42},
pages   = {13282--13288},
year    = {2010},
doi     = {10.1021/jp104924g}
}

4. Mapping hydrophobicity at the nanoscale: Applications to heterogeneous surfaces and proteins
Acharya H, Vembanur S, Jamadagni SN and Garde S, Faraday Discuss. ,146 ,353-365 (2010)
Approaches to quantify wetting at the macroscale do not translate to the nanoscale, highlighting the need for new methods for characterizing hydrophobicity at the small scale. We use extensive molecular simulations to study the hydration of homo and heterogeneous self-assembled monolayers (SAMs) and of protein surfaces. For homogeneous SAMs, new pressure-dependent analysis shows that water displays higher compressibility and enhanced density fluctuations near hydrophobic surfaces, which are gradually quenched with increasing hydrophilicity, consistent with our previous studies. Heterogeneous surfaces show an interesting context dependence – adding a single –OH group in a –CH3 terminated SAM has a more dramatic effect on water in the vicinity compared to that of a single –CH3 group in an –OH background. For mixed –CH3/–OH SAMs, this asymmetry leads to a non-linear dependence of hydrophobicity on the surface concentration. We also present preliminary results to map hydrophobicity of protein surfaces by monitoring local density fluctuations and binding of probe hydrophobic solutes. These molecular measures account for the behavior of protein's hydration water, and present a more refined picture of its hydrophobicity map. At least for one protein, hydrophobin-II, we show that the hydrophobicity map is different from that suggested by a commonly used hydropathy scale
@article{acharya2010mapping,
title   = {Mapping hydrophobicity at the nanoscale: Applications to
heterogeneous surfaces and proteins},
author  = {Acharya, Hari and Vembanur, Srivathsan and
Jamadagni, Sumanth N and Garde, Shekhar},
journal = {Faraday discussions},
volume  = {146},
pages   = {353--365},
year    = {2010},
doi     = {10.1039/B927019A}
}

5. Studying pressure denaturation of a protein by molecular dynamics simulations
Sarupria S, Ghosh T, Garcia AE and Garde S, Proteins ,78 (7) ,1641-1651 (2010)
Many globular proteins unfold when subjected to several kilobars of hydrostatic pressure. This “unfolding-up-on-squeezing” is counter-intuitive in that one expects mechanical compression of proteins with increasing pressure. Molecular simulations have the potential to provide fundamental understanding of pressure effects on proteins. However, the slow kinetics of unfolding, especially at high pressures, eliminates the possibility of its direct observation by molecular dynamics (MD) simulations. Motivated by experimental results—that pressure denatured states are water-swollen, and theoretical results—that water transfer into hydrophobic contacts becomes favorable with increasing pressure, we employ a water insertion method to generate unfolded states of the protein Staphylococcal Nuclease (Snase). Structural characteristics of these unfolded states—their water-swollen nature, retention of secondary structure, and overall compactness—mimic those observed in experiments. Using conformations of folded and unfolded states, we calculate their partial molar volumes in MD simulations and estimate the pressure-dependent free energy of unfolding. The volume of unfolding of Snase is negative (approximately −60 mL/mol at 1 bar) and is relatively insensitive to pressure, leading to its unfolding in the pressure range of 1500–2000 bars. Interestingly, once the protein is sufficiently water swollen, the partial molar volume of the protein appears to be insensitive to further conformational expansion or unfolding. Specifically, water-swollen structures with relatively low radii of gyration have partial molar volume that are similar to that of significantly more unfolded states. We find that the compressibility change on unfolding is negligible, consistent with experiments. We also analyze hydration shell fluctuations to comment on the hydration contributions to protein compressibility. Our study demonstrates the utility of molecular simulations in estimating volumetric properties and pressure stability of proteins, and can be potentially extended for applications to protein complexes and assemblies.
@article{sarupria2010studying,
title   = {Studying pressure denaturation of a protein by molecular
dynamics simulations},
author  = {Sarupria, Sapna and Ghosh, Tuhin and Garc{\'\i}a, Angel E
and Garde, Shekhar},
journal = {Proteins: Structure, Function, and Bioinformatics},
volume  = {78},
number  = {7},
pages   = {1641--1651},
year    = {2010},
doi     = {10.1002/prot.22680}
}

6. Self-Assembly of TMAO at Hydrophobic Interfaces and Its Effect on Protein Adsorption: Insights from Experiments and Simulations
Anand G, Jamadagni SN, Garde S and Belfort G, Langmuir ,26 (12) ,9695-9702 (2010)
We offer a novel process to render hydrophobic surfaces resistant to relatively small proteins during adsorption. This was accomplished by self-assembly of a well-known natural osmolyte, trimethylamine oxide (TMAO), a small amphiphilic molecule, on a hydrophobic alkanethiol surface. Measurments of lysozyme (LYS) adsorption on several homogeneous substrates formed from functionalized alkanethiol self-assembled monolayers (SAMs) in the presence and absence of TMAO, and direct interaction energy between the protein and functionalized surfaces, demonstrate the protein-resistant properties of a noncovalently adsorbed self-assembled TMAO layer. Molecular dynamics simulations clearly show that TMAO molecules concentrate near the CH3−SAM surface and are preferentially excluded from LYS. Interestingly, TMAO molecules adsorb strongly on a hydrophobic CH3−SAM surface, but a trade-off between hydrogen bonding with water, and hydrophobic interactions with the underlying substrate results in a nonintuitive orientation of TMAO molecules at the interface. Additionally, hydrophobic interactions, usually responsible for nonspecific adsorption of proteins, are weakly affected by TMAO. In addition to TMAO, other osmolytes (sucrose, taurine, and betaine) and a larger homologue of TMAO (N,N-dimethylheptylamine-N-oxide) were tested for protein resistance and only N,N-dimethylheptylamine-N-oxide exhibited resistance similar to TMAO. The principle of osmolyte exclusion from the protein backbone is responsible for the protein-resistant property of the surface. We speculate that this novel process of surface modification may have wide applications due to its simplicity, low cost, regenerability, and flexibility.
@article{anand2010self,
title   = {Self-assembly of TMAO at hydrophobic interfaces and its effect
on protein adsorption: insights from experiments and simulations},
author  = {Anand, Gaurav and Jamadagni, Sumanth N and Garde, Shekhar
and Belfort, Georges},
journal = {Langmuir},
volume  = {26},
number  = {12},
pages   = {9695--9702},
year    = {2010},
doi     = {10.1021/la100363m}
}

7. Unfolding of Hydrophobic Polymers in Guanidinium Chloride Solutions
Godawat R, Jamadagni SN and Garde S, J. Phys. Chem. B ,114 (6) ,2246-2254 (2010)
Guanidinium chloride (GdmCl) is a widely used chemical denaturant that unfolds proteins. Its effects on hydrophobic interactions are, however, not fully understood. We quantify the effects of GdmCl on various manifestations of hydrophobicity — from solvation and interactions of small solutes to folding−unfolding of hydrophobic polymers — in water and in concentrated GdmCl solutions. For comparison, we also perform similar calculations in solutions of NaCl and CsCl in water. Like NaCl and CsCl, GdmCl increases the surface tension of water, decreases the solubility of small hydrophobic solutes, and enhances the strength of hydrophobic interactions at the pair level. However, unlike NaCl and CsCl, GdmCl destabilizes folded states of hydrophobic polymers. We show that Gdm+ ions preferentially coat the hydrophobic polymer, and it is the direct van der Waals interaction between Gdm+ ions and the polymer that contributes to the destabilization of folded states. Interestingly, the temperature dependence of the free energy of unfolding of the hydrophobic polymer in water is protein-like, with signatures of both heat and cold denaturation. Addition of GdmCl shifts the cold denaturation temperature higher, into the experimentally accessible region. Finally, translational as well as conformational dynamics of the polymer are slower in GdmCl and correlate with dynamics of water molecules in solution.
@article{godawat2010unfolding,
title   = {Unfolding of hydrophobic polymers in guanidinium chloride solutions},
author  = {Godawat, Rahul and Jamadagni, Sumanth N and Garde, Shekhar},
journal = {The Journal of Physical Chemistry B},
volume  = {114},
number  = {6},
pages   = {2246--2254},
year    = {2010},
doi     = {10.1021/jp906976q}
}


2009

1. How Interfaces Affect Hydrophobically Driven Polymer Folding
Jamadagni SN, Godawat R and Garde S, J. Phys. Chem. B ,113(13) ,4093-4101 (2009)
Studies of folding−unfolding of hydrophobic polymers in water provide an excellent starting point to probe manybody hydrophobic interactions in the context of realistic self-assembly processes. Such studies in bulk water have highlighted the similarities between thermodynamics of polymer collapse and of protein folding, and emphasized the role of hydration—water structure, density, and fluctuations—in the folding kinetics. Hydrophobic polymers are interfacially active—that is, they prefer locations at aqueous interfaces relative to bulk water—consistent with their low solubility. How does the presence of a hydrophobic solid surface or an essentially hydrophobic vapor−water interface affect the structural, thermodynamic, and kinetic aspects of polymer folding? Using extensive molecular dynamics simulations, we show that the large hydrophobic driving force for polymer collapse in bulk water is reduced at a solid alkane−water interface and further reduced at a vapor−water interface. As a result, at the solid−water interface, folded structures are marginally stable, whereas the vapor−liquid interface unfolds polymers completely. Structural sampling is also significantly affected by the interface. For example, at the solid−water interface, polymer conformations are quasi-2-dimensional, with folded states being pancake-like structures. At the vapor−water interface, the hydrophobic polymer is significantly excluded from the water phase and freely samples a broad range of compact to extended structures. Interestingly, although the driving force for folding is considerably lower, kinetics of folding are faster at both interfaces, highlighting the role of enhanced water fluctuations and dynamics at a hydrophobic interface.
@article{jamadagni2008interfaces,
title   = {How Interfaces Affect Hydrophobically Driven Polymer Folding†},
author  = {Jamadagni, Sumanth N and Godawat, Rahul and Dordick, Jonathan S and Garde, Shekhar},
journal = {The Journal of Physical Chemistry B},
volume  = {113},
number  = {13},
pages   = {4093--4101},
year    = {2008},
doi     = {10.1021/jp806528m}
}

2. Hydration Dynamics at Femtosecond Time Scales and Angstrom Length Scales from Inelastic X-Ray Scattering
Coridan RH, Schmidt NW, Lai GH, Godawat R, Krisch M, Garde S, Abbamonte P and Wong GCL, Phys. Rev. Lett. ,103(23) ,237402 (2009)
We use high resolution dynamical structure factor S(q,ω) data measured with inelastic x-ray scattering to reconstruct the Green’s function of water, which describes its density response to a point charge, and provides a fundamental comparative model for solvation behavior at molecular time scales and length scales. Good agreement is found with simulations, scattering and spectroscopic experiments. These results suggest that a moving point charge will modify its hydration structure, evolving from a spherical closed shell to a steady-state cylindrical hydration “sleeve”.
@article{coridan2009hydration,
title   = {Hydration dynamics at femtosecond time scales and Angstrom
length scales from inelastic X-Ray scattering},
author  = {Coridan, Robert H and Schmidt, Nathan W and Lai, Ghee Hwee and
Godawat, Rahul and Krisch, Michael and Garde, Shekhar and
Abbamonte, Peter and Wong, Gerard CL},
journal = {Physical review letters},
volume  = {103},
number  = {23},
pages   = {237402},
year    = {2009},
doi     = {10.1103/PhysRevLett.103.237402}
}

3. Configuration of PKCα-C2 Domain Bound to Mixed SOPC/SOPS Lipid Monolayers
Chen CH, Malkova S, Pingali SV, Long F, Garde S, Cho W and Schlossman ML, Biophysical J. ,97(10) ,2794-2802 (2009)
X-ray reflectivity measurements are used to determine the configuration of the C2 domain of protein kinase Cα (PKCα-C2) bound to a lipid monolayer of a 7:3 mixture of 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1-stearoyl-2-oleoyl-sn-glycero-3-phosphoserine supported on a buffered aqueous solution. The reflectivity is analyzed in terms of the known crystallographic structure of PKCα-C2 and a slab model representation of the lipid layer. The configuration of lipid-bound PKCα-C2 is described by two angles that define its orientation, θ = 35° ± 10° and φ =210° ± 30°, and a penetration depth (=7.5 ± 2 Å) into the lipid layer. In this structure, the β-sheets of PKCα-C2 are nearly perpendicular to the lipid layer and the domain penetrates into the headgroup region of the lipid layer, but not into the tailgroup region. This configuration of PKCα-C2 determined by our x-ray reflectivity is consistent with many previous findings, particularly mutational studies, and also provides what we believe is new molecular insight into the mechanism of PKCα enzyme activation. Our analysis method, which allows us to test all possible protein orientations, shows that our data cannot be explained by a protein that is orientated parallel to the membrane, as suggested by earlier work.
@article{chen2009configuration,
title   = {Configuration of PKC< i> $\alpha$-C2 Domain Bound to Mixed SOPC/SOPS Lipid Monolayers},
author  = {Chen, Chiu-Hao and M{\'a}lkov{\'a}, {\v{S}}{\'a}rka and
Pingali, Sai Venkatesh and Long, Fei and Garde, Shekhar and
Cho, Wonhwa and Schlossman, Mark L},
journal = {Biophysical journal},
volume  = {97},
number  = {10},
pages   = {2794--2802},
year    = {2009},
doi     = {10.1016/j.bpj.2009.08.037}
}

4. Addition/Correction: Ion Pairing in Molecular Simulations of Aqueous Alkali Halide Solutions
Fennell CJ, Bizjak A, Vlachy V, Dill KA, Sarupria S, Rajamani S and Garde S, J. Phys. Chem. B ,113 (44) ,14837-14838 (2009)

5. How hydrophobic hydration responds to solute size and attractions: Theory and simulations
Athawale MV, Jamadagni SN and Garde S, J. Chem. Phys. ,131 ,115102 (2009)
We focus on the hydration of a methane and spherical single and multisite C60 and C180 solutes over a range of solute-water attractions to quantify the vicinal water structure and their hydration thermodynamics using extensive molecular dynamics simulations and theory. We show that water structure near larger solutes is more sensitive to solute-water attractions compared to that near smaller ones. To understand the sensitivity, we separate the solute-water potential of mean force into a direct solute-water interaction and an indirect or solvent contribution [ω(r)]. In the absence of ω(r), water density in the solute vicinity would increase exponentially with solute-water interactions. Instead, ω(r) becomes increasingly repulsive with strengthening of solute-water attractions thereby opposing those direct interactions. We term this phenomenon “competitive expulsion,” which characterizes the repulsion of a test water molecule by the hydration shell solventwaters. We develop a physically motivated theoretical approach to predict changes in ω(r) with attractions. We call this approach the modified-EXP (M-EXP) approximation owing to the similarity of ideas and especially our final expression with that of the EXP approximation of Chandler and Andersen [J. Chem. Phys.57, 1930 (1972)]. Solute-water radial distribution functions and chemical potentials calculated using the M-EXP approach are in good agreement with simulation data. These calculations highlight the sensitivity of hydration structure and thermodynamics of bucky ball like solutes to solute-water interactions. We find that excess chemical potentials of bucky balls with standard alkane-like carbon-water interactions parameters are negative, suggesting the need for a careful calibration of those parameters for predictions of solubility, wetting, and water-mediated interactions using molecular simulations.
@article{athawale2009hydrophobic,
title   = {How hydrophobic hydration responds to solute size and attractions: Theory and simulations},
author  = {Athawale, Manoj V and Jamadagni, Sumanth N and Garde, Shekhar},
journal = {The Journal of chemical physics},
volume  = {131},
pages   = {115102},
year    = {2009},
doi     = {10.1063/1.3227031}
}

6. Characterizing hydrophobicity of interfaces by using cavity formation, solute binding, and water correlations
Godawat R, Jamadagni SN and Garde S, Proc. Natl. Acad. Sci. USA ,106(36) ,15119-15124 (2009)
Hydrophobicity is often characterized macroscopically by the droplet contact angle. Molecular signatures of hydrophobicity have, however, remained elusive. Successful theories predict a drying transition leading to a vapor-like region near large hard-sphere solutes and interfaces. Adding attractions wets the interface with local density increasing with attractions. Here we present extensive molecular simulation studies of hydration of realistic surfaces with a wide range of chemistries from hydrophobic (−CF3, −CH3) to hydrophilic (−OH, −CONH2). We show that the water density near weakly attractive hydrophobic surfaces (e.g., −CF3) can be bulk-like or larger, and provides a poor quantification of surface hydrophobicity. In contrast, the probability of cavity formation or the free energy of binding of hydrophobic solutes to interfaces correlates quantitatively with the macroscopic wetting properties and serves as an excellent signature of hydrophobicity. Specifically, the probability of cavity formation is enhanced in the vicinity of hydrophobic surfaces, and water–water correlations correspondingly display characteristics similar to those near a vapor–liquid interface. Hydrophilic surfaces suppress cavity formation and reduce the water–water correlation length. Our results suggest a potentially robust approach for characterizing hydrophobicity of more complex and heterogeneous surfaces of proteins and biomolecules, and other nanoscopic objects.
@article{godawat2009characterizing,
title   = {Characterizing hydrophobicity of interfaces by using cavity formation, solute binding, and water correlations},
author  = {Godawat, Rahul and Jamadagni, Sumanth N and Garde, Shekhar},
journal = {Proceedings of the National Academy of Sciences},
volume  = {106},
number  = {36},
pages   = {15119--15124},
year    = {2009},
doi     = {10.1073/pnas.0902778106}
}

7. Quantifying Water Density Fluctuations and Compressibility of Hydration Shells of Hydrophobic Solutes and Proteins
Sarupria S and Garde S, Phys. Rev. Lett. ,103(3) ,37803 (2009)
We probe the effects of solute length scale, attractions, and hydrostatic pressure on hydrophobic hydration shells using extensive molecular simulations. The hydration shell compressibility and water fluctuations both display a nonmonotonic dependence on solute size, with a minimum near molecular solutes and enhanced fluctuations for larger ones. These results and calculations on proteins suggest that the hydration shells of unfolded proteins are more compressible than of folded ones contributing to pressure denaturation. More importantly, the nonmonotonicity implies a solute curvature-dependent pressure sensitivity for interactions between hydrophobic solutes.
@article{sarupria2009quantifying,
title   = {Quantifying water density fluctuations and compressibility of hydration shells of hydrophobic solutes and proteins},
author  = {Sarupria, Sapna and Garde, Shekhar},
journal = {Physical review letters},
volume  = {103},
number  = {3},
pages   = {037803},
year    = {2009},
doi     = {10.1103/PhysRevLett.103.037803}
}

8. How Surface Wettability Affects the Binding, Folding, and Dynamics of Hydrophobic Polymers at Interfaces
Jamadagni SN, Godawat R and Garde S, Langmuir ,25(22) ,13092-13099 (2009)
We present an extensive molecular simulation study of the behavior of a flexible hydrophobic 25-mer polymer at interfaces presenting a range of chemistries from hydrophobic (−CH3) to hydrophilic (−CONH2). We quantify the free energy of adsorption, conformational equilibria, and translational and conformational dynamics of the polymer at these diverse interfaces. Water-mediated interactions drive the polymer to adsorb strongly at a hydrophobic interface and repel it from hydrophilic ones. At hydrophilic surfaces, van der Waals interactions between the polymer and the surface mitigate this water-mediated repulsion, leading to weak adsorption of the polymer. Although the polymer is strongly adsorbed to hydrophobic surfaces, it is also most dynamic there. Translational diffusion and conformational dynamics are faster at hydrophobic surfaces compared to those at hydrophilic ones. In bulk water, the polymer collapses into compact globular shapes, whereas the thermodynamic stability of folded polymers is significantly lowered at hydrophobic surfaces. The polymer spreads into pancake-like 2D conformations at hydrophobic surfaces and gradually beads up into globular shapes as the surface is made more hydrophilic. Interestingly, the binding thermodynamics and dynamics correlate with macroscopic droplet contact angles that characterize the wetting properties of the different interfaces.
@article{jamadagni2009surface,
title   = {How surface wettability affects the binding, folding, and dynamics of hydrophobic polymers at interfaces},
author  = {Jamadagni, Sumanth N and Godawat, Rahul and Garde, Shekhar},
journal = {Langmuir},
volume  = {25},
number  = {22},
pages   = {13092--13099},
year    = {2009},
doi     = {10.1021/la9011839}
}

9. How Wetting and Adhesion Affect Thermal Conductance of a Range of Hydrophobic to Hydrophilic Aqueous Interfaces
Shenogina N, Godawat R, Keblinski P and Garde S, Phys. Rev. Lett. ,102(15) ,156101 (2009)
We quantify the strength of interfacial thermal coupling at water-solid interfaces over a broad range of surface chemistries from hydrophobic to hydrophilic using molecular simulations. We show that the Kapitza conductance is proportional to the work of adhesion—a wetting property of that interface—enabling the use of thermal transport measurements as probes of the molecular environment and bonding at an interface. Excellent agreement with experiments on similar systems [ Z. B. Ge et al. Phys. Rev. Lett. 96 186101 (2006)] highlights the convergence of simulation and experiments on these complex nanoscopic systems.
@article{shenogina2009wetting,
title   = {How wetting and adhesion affect thermal conductance of a range of hydrophobic to hydrophilic aqueous interfaces},
author  = {Shenogina, Natalia and Godawat, Rahul and Keblinski, Pawel and Garde, Shekhar},
journal = {Physical review letters},
volume  = {102},
number  = {15},
pages   = {156101},
year    = {2009},
doi     = {10.1103/PhysRevLett.102.156101}
}

10. Mechanistic studies of displacer–protein binding in chemically selective displacement systems using NMR and MD simulations
Morrison CJ, Godawat R, McCallum SA, Garde S and Cramer S, Biotechnol. Bioeng. ,102(5) ,1428-1437 (2009)
A parallel batch screening technique was employed to identify chemically selective displacers which exhibited exclusive separation behavior for the protein pair α-chymotrypsin/ribonuclease A on a strong cation exchange resin. Two selective displacers, 1-(4-chlorobenzyl)piperidin-3-aminesulfate and N′1′-(4-methyl-quinolin-2-yl)-ethane-1,2-diamine dinitrate, and one non-selective displacer, spermidine, were selected as model systems to investigate the mechanism of chemically selective displacement chromatography. Saturation transfer difference (STD) NMR was used to directly evaluate displacer–protein binding. The results indicated that while binding occurred between the two chemically selective displacers and the more hydrophobic protein, α-chymotrypsin, no binding was observed with ribonuclease A. Further, the non-selective displacer, spermidine, was not observed to bind to either protein. Importantly, the binding event was observed to occur primarily on the aromatic portion of the selective displacers. Extensive molecular dynamic simulations of protein–displacer–water solution were also carried out. The MD results corroborated the NMR findings demonstrating that the binding of selective displacers occurred primarily on hydrophobic surface patches of α-chymotrypsin, while no significant long term binding to ribonuclease A was observed. The non-selective displacer did not show significant binding to either of the proteins. MD simulations also indicated that the charged amine group of the selective displacers in the bound state was primarily oriented towards the solvent, potentially facilitating their interaction with a resin surface. These results directly confirm that selective binding between a protein and displacer is the mechanism by which chemically selective displacement occurs. This opens up many possibilities for future molecular design of selective displacers for a range of applications
@article{morrison2009mechanistic,
title   = {Mechanistic studies of displacer--protein binding in chemically selective displacement systems using NMR and MD simulations},
author  = {Morrison, Christopher J and Godawat, Rahul and McCallum, Scott A and Garde, Shekhar and Cramer, Steven M},
journal = {Biotechnology and bioengineering},
volume  = {102},
number  = {5},
pages   = {1428--1437},
year    = {2009},
doi     = {10.1002/bit.22170}
}


2008

1. Water in Nonpolar Confinement: From Nanotubes to Proteins and Beyond
Rasaiah JC, Garde S and Hummer G, Ann. Rev. Phys. Chem. ,59 ,713-740 (2008)
Water molecules confined to nonpolar pores and cavities of nanoscopic dimensions exhibit highly unusual properties. Water filling is strongly cooperative, with the possible coexistence of filled and empty states and sensitivity to small perturbations of the pore polarity and solvent conditions. Confined water molecules form tightly hydrogen-bonded wires or clusters. The weak attractions to the confining wall, combined with strong interactions between water molecules, permit exceptionally rapid water flow, exceeding expectations from macroscopic hydrodynamics by several orders of magnitude. The proton mobility along 1D water wires also substantially exceeds that in the bulk. Proteins appear to exploit these unusual properties of confined water in their biological function (e.g., to ensure rapid water flow in aquaporins or to gate proton flow in proton pumps and enzymes). The unusual properties of water in nonpolar confinement are also relevant to the design of novel nanofluidic and molecular separation devices or fuel cells.
@article{rasaiah2008water,
title   = {Water in Nonpolar Confinement: From Nanotubes to Proteins and Beyond*},
author  = {Rasaiah, Jayendran C and Garde, Shekhar and Hummer, Gerhard},
journal = {Annu. Rev. Phys. Chem.},
volume  = {59},
pages   = {713--740},
year    = {2008},
doi     = {10.1146/annurev.physchem.59.032607.093815}
}

2. Strong frequency dependence of dynamical coupling between protein and water
Shenogina N, Keblinski P and Garde S, J. Chem. Phys. ,129 ,155105 (2008)
We use molecular dynamics simulations to study thermal energy flow between a green fluorescent protein and surrounding water to unravel the nature of dynamical coupling between biomolecules and their aqueous environment. We find that low-frequency vibrations in protein, which are thought to be critical for the protein function, are strongly coupled with water, whereas intermediate- and high-frequency vibrations are essentially decoupled with water except for those present at the surface of the protein. Our studies shed a new light on the physical mechanism underlying the dynamical slaving of proteins to water.
@article{shenogina2008strong,
title   = {Strong frequency dependence of dynamical coupling between protein and water},
author  = {Shenogina, Natalia and Keblinski, Pawel and Garde, Shekhar},
journal = {The Journal of chemical physics},
volume  = {129},
pages   = {155105},
year    = {2008},
doi     = {10.1063/1.2991183}
}

3. Attractions, Water Structure, and Thermodynamics of Hydrophobic Polymer Collapse
Goel G, Athawale MV, Garde S and Truskett TM, J. Phys. Chem. B ,112(42) ,13193-13196 (2008)
We explore the prospects of a perturbation approach for predicting how weak attractive interactions affect collapse thermodynamics of hydrophobic polymers in water. Specifically, using molecular dynamics simulations of model polymers in explicit water, we show that the hydration structure is sensitive to the strength of the van der Waals attractions but that the hydration contribution to the potential of mean force for collapse is not. We discuss how perturbation theory ideas developed for small spherical apolar solutes need to be modified in order to account for the effect of attractions on the conformational equilibria of polymers.
@article{goel2008attractions,
title   = {Attractions, water structure, and thermodynamics of hydrophobic polymer collapse},
author  = {Goel, Gaurav and Athawale, Manoj V and Garde, Shekhar and Truskett, Thomas M},
journal = {The Journal of Physical Chemistry B},
volume  = {112},
number  = {42},
pages   = {13193--13196},
year    = {2008},
doi     = {10.1021/jp806993b}
}

4. Enthalpy-Entropy Contributions to Salt and Osmolyte Effects on Molecular-Scale Hydrophobic Hydration and Interactions
Athawale MV, Sarupria S and Garde S, J. Phys. Chem. B ,112(18) ,5661-5670 (2008)
Salts and additives can significantly affect the strength of water-mediated interactions in solution. We present results from molecular dynamics simulations focused on the thermodynamics of hydrophobic hydration, association, and the folding−unfolding of a hydrophobic polymer in water and in aqueous solutions of NaCl and of an osmolyte trimethylamine oxide (TMAO). It is known that addition of NaCl makes the hydration of hydrophobic solutes unfavorable and, correspondingly, strengthens their association at the pair as well as the many-body level (Ghosh, T.; Kalra, A.; Garde, S. J. Phys. Chem. B 2005, 109, 642), whereas the osmolyte TMAO has an almost negligible effect on the hydrophobic hydration and association (Athawale, M. V.; Dordick, J. S.; Garde, S. Biophys. J. 2005, 89, 858). Whether these effects are enthalpic or entropic in origin is not fully known. Here we perform temperature-dependent simulations to resolve the free energy into entropy and enthalpy contributions. We find that in TMAO solutions, there is an almost precise entropy−enthalpy compensation leading to the negligible effect of TMAO on hydrophobic phenomena. In contrast, in NaCl solutions, changes in enthalpy dominate, making the salt-induced strengthening of hydrophobic interactions enthalpic in origin. The resolution of total enthalpy into solute−solvent and solvent−solvent terms further shows that enthalpy changes originate primarily from solvent−solvent energy terms. Our results are consistent with experimental data on the hydration of small hydrophobic solutes by Ben-Naim and Yaacobi (Ben-Naim, A.; Yaacobi, M. J. Phys. Chem. 1974, 78, 170). In combination with recent work by Zangi, Hagen, and Berne (Zangi, R.; Hagen, M.; Berne, B. J. J. Am. Chem. Soc. 2007, 129, 4678) and the experimental data on surface tensions of salt solutions by Matubayasi et al. (Matubayasi, N.; Matsuo, H.; Yamamoto, K.; Yamaguchi, S.; Matuzawa, A. J. Colloid Interface Sci. 1999, 209, 398), our results highlight interesting length scale dependences of salt effects on hydrophobic phenomena. Although NaCl strengthens hydrophobic interactions at both small and large length scales, that effect is enthalpy-dominated at small length scales and entropy-dominated for large solutes and interfaces. Our results have implications for understanding of additive effects on water-mediated interactions, as well as on biocompatibility of osmolyte molecules in aqueous solutions.
@article{athawale2008enthalpy,
title   = {Enthalpy-entropy contributions to salt and osmolyte effects on
molecular-scale hydrophobic hydration and interactions},
author  = {Athawale, Manoj V and Sarupria, Sapna and Garde, Shekhar},
journal = {The Journal of Physical Chemistry B},
volume  = {112},
number  = {18},
pages   = {5661--5670},
year    = {2008},
doi     = {10.1021/jp073485n}
}

5. Structure, Stability, and Rupture of Free and Supported Liquid Films and Assemblies in Molecular Simulations
Godawat R, Jamadagni SN, Errington JR and Garde S, Ind. Eng. Chem. Res. ,47(10) ,3582-3590 (2008)
Attractive interactions between molecules lead to formation of the liquid phase at sufficiently low temperatures. In the absence of external fields or containers, liquids assume the shape of spherical drops, which minimize their surface area. In systems with 3-D periodic boundary conditions (PBCs), which are routinely employed in molecular simulations, alternate configurations can be stable depending on the extent of the system. The stability of a variety of structures under 3-D PBCs originates from the underlying variation of free energy with density as shown elegantly by MacDowell and co-workers (MacDowell, L. G.; Shen, V. K.; Errington, J. R. J. Chem. Phys. 2006, 125, 3.). Here we present analysis of extensive Monte Carlo and molecular dynamics simulations of Lennard-Jones and water fluids to calculate free energy and explore the phase diagram that governs formation of different liquid assemblies. We also study metastability of different shapes and their interconversions by systematically initializing simulations in various configurations. Further, We present results on the rupture of thin liquid films on solid substrates, with focus on the evolution of liquid structure and the rupture mechanism. Our estimates of important capillary wavelengths from simulations are in good agreement with theoretical predictions of Vrij and Overbeek (Vrij, A.; Overbeek, J. T. J. Am. Chem. Soc. 1968, 90, 3074−3078.). Collectively, our work significantly extends the previous simulation studies of interfacial systems, and especially of thin-film structure, stability, and rupture processes in molecular simulations.
@article{godawat2008structure,
title   = {Structure, stability, and rupture of free and supported liquid
films and assemblies in molecular simulations},
author  = {Godawat, Rahul and Jamadagni, Sumanth N and
Errington, Jeffrey R and Garde, Shekhar},
journal = {Industrial \& Engineering Chemistry Research},
volume  = {47},
number  = {10},
pages   = {3582--3590},
year    = {2008},
doi     = {10.1021/ie7017383}
}


2007

1. Pressure dependence of the compressibility of a micelle and a protein: insights from cavity formation analysis
Pereira B, Jain S, Sarupria S, Yang L and Garde S, Mol. Phys. ,105 (2) ,189-199 (2007)
We present results from molecular dynamics simulations of a spherical micelle comprising 80 non-ionic C8E5 surfactants in water, a protein staphylococcal nuclease in water, and bulk n-hexane and water liquids over a range of hydrostatic pressures. We focus specifically on the pressure dependence of the volumetric properties—the partial molar volume and partial molar compressibility—of the micelle, the protein, and bulk liquids. We find that the micelle interior displays properties similar to liquid alkanes over a range of pressures and has a compressibility of 100−110×10−6 bar−1 under ambient conditions, which is more than twice that of liquid water. In contrast, the pressure dependence of the protein interior resembles that of solid organic polymeric materials and has a compressibility of 5−10×10−6 bar−1. We performed extensive analysis of cavity formation in all systems. Interestingly, it is not the average cavity size but the width of the cavity size distribution in a given medium that correlates with the compressibility of that medium over a broad range of pressures up to several kilobars. Correspondingly, the cavity size distribution is most sharply defined in protein interiors and is broadest in the micelle interior and in n-hexane. To explore the correlation between cavity formation and compressibility, we present preliminary calculations using the information theory approach in the bulk water phase. Analysis of cavity formation and, especially, the nature of the cavity size distribution may provide a sensitive probe of the compressibility and flexibility of local molecular environments in inhomogeneous condensed media.
@article{pereira2007pressure,
title   = {Pressure dependence of the compressibility of a micelle and a protein: insights from cavity formation analysis},
author  = {Pereira, Brian and Jain, Sandeep and Sarupria, Sapna and Yang, Lu and Garde, Shekhar},
journal = {Molecular Physics},
volume  = {105},
number  = {2-3},
pages   = {189--199},
year    = {2007},
doi     = {10.1080/00268970601140750}
}

2. Modeling the selective partitioning of cations into negatively charged nanopores in water
Yang L and Garde S, J. Chem. Phys. ,126 ,084706 (2007)
Partitioning and transport of water and small solutes into and through nanopores are important to a variety of chemical and biological processes and applications. Here we study water structure in negatively charged model cylindrical [carbon nanotube (CNT)-like] nanopores, as well as the partitioning of positive ions of increasing size (Na+, K+, and Cs+) into the pore interior using extensive molecular dynamics simulations. Despite the simplicity of the simulation system—containing a short CNT-like nanopore in water carrying a uniformly distributed charge of qpore = −ne surrounded by n ( = 0,…,8) cations, making the overall system charge neutral—the results provide new and useful insights on both the pore hydration and ion partitioning. For n = 0, that is, for a neutral nanopore, water molecules partition into the pore and form single-file hydrogen-bonded wire spanning the pore length. With increasing n, water molecules enter the pore from both ends with preferred orientations, resulting in a mutual repulsion between oriented water molecules at the pore center and creating a cavity-like low density region at the center. For low negative charge densities on the pore, the driving force for partitioning of positive ions into the pore is weak, and no partitioning is observed. Increasing the pore charge gradually leads to partitioning of positive ions into the pore. Interestingly, over a range of intermediate negative charge densities, nanopores display both thermodynamic as well as kinetic selectivity toward partitioning of the larger K+ and Cs+ ions into their interior over the smaller Na+ ions. Specifically, the driving force is in the order K+>Cs+>Na+, and K+ and Cs+ ions enter the pore much more rapidly than Na+ ions. At higher charge densities, the driving force for partitioning increases for all cations—it is highest for K+ ions—and becomes similar for Na+ and Cs+ ions. The variation of thermodynamic driving force and the average partitioning time with the pore charge density together suggest the presence of free energy barriers in the partitioning process. We discuss the role of ion hydration in the bulk and in the pore interior as well as of the pore hydration in determining the barrier heights for ion partitioning and the observed thermodynamic and kinetic selectivities.

3. Mechanism for intein C-terminal cleavage: A proposal from quantum mechanical calculations
Shemella P, Pereira B, Zhang Y, Van Roey P, Belfort G, Garde S and Nayak SK, Biophysical J. ,92 (3) ,847-853 (2007)
nteins are autocatalytic protein cleavage and splicing elements. A cysteine to alanine mutation at the N-terminal of inteins inhibits splicing and isolates the C-terminal cleavage reaction. Experiments indicate an enhanced C-terminal cleavage reaction rate upon decreasing the solution pH for the cleavage mutant, which cannot be explained by the existing mechanistic framework. We use intein crystal structure data and the information about conserved amino acids to perform semiempirical PM3 calculations followed by high-level density functional theory calculations in both gas phase and implicit solvent environments. Based on these calculations, we propose a detailed “low pH” mechanism for intein C-terminal cleavage. Water plays an important role in the proposed reaction mechanism, acting as an acid as well as a base. The protonation of the scissile peptide bond nitrogen by a hydronium ion is an important first step in the reaction. That step is followed by the attack of the C-terminal asparagine side chain on its carbonyl carbon, causing succinimide formation and simultaneous peptide bond cleavage. The computed reaction energy barrier in the gas phase is ∼33kcal/mol and reduces to ∼25kcal/mol in solution, close to the 21kcal/mol experimentally observed at pH 6.0. This mechanism is consistent with the observed increase in C-terminal cleavage activity at low pH for the cleavage mutant of the Mycobacterium tuberculosis RecA mini-intein.
@article{shemella2007mechanism,
title   = {Mechanism for intein C-terminal cleavage: a proposal from quantum mechanical calculations},
author  = {Shemella, Philip and Pereira, Brian and Zhang, Yiming and Van Roey, Patrick and Belfort, Georges and Garde, Shekhar and Nayak, Saroj K},
journal = {Biophysical journal},
volume  = {92},
number  = {3},
pages   = {847--853},
year    = {2007},
doi     = {10.1529/biophysj.106.092049}
}

4. Effects of lengthscales and attractions on the collapse of hydrophobic polymers in water
Athawale MV, Goel G, Ghosh T, Truskett TM and Garde S, Proc. Natl. Acad. Sci. USA ,104 (3) ,733--738 (2007)
We present results from extensive molecular dynamics simulations of collapse transitions of hydrophobic polymers in explicit water focused on understanding effects of lengthscale of the hydrophobic surface and of attractive interactions on folding. Hydrophobic polymers display parabolic, protein-like, temperature-dependent free energy of unfolding. Folded states of small attractive polymers are marginally stable at 300 K and can be unfolded by heating or cooling. Increasing the lengthscale or decreasing the polymer–water attractions stabilizes folded states significantly, the former dominated by the hydration contribution. That hydration contribution can be described by the surface tension model, ΔG = γ(T)ΔA, where the surface tension, γ, is lengthscale-dependent and decreases monotonically with temperature. The resulting variation of the hydration entropy with polymer lengthscale is consistent with theoretical predictions of Huang and Chandler [Huang DM, Chandler D (2000) Proc Natl Acad Sci USA 97:8324–8327] that explain the blurring of entropy convergence observed in protein folding thermodynamics. Analysis of water structure shows that the polymer–water hydrophobic interface is soft and weakly dewetted, and is characterized by enhanced interfacial density fluctuations. Formation of this interface, which induces polymer folding, is strongly opposed by enthalpy and favored by entropy, similar to the vapor–liquid interface.
@article{athawale2007effects,
title   = {Effects of lengthscales and attractions on the collapse of
hydrophobic polymers in water},
author  = {Athawale, Manoj V and Goel, Gaurav and Ghosh, Tuhin
and Truskett, Thomas M and Garde, Shekhar},
journal = {Proc. Natl. Acad. Sci. USA},
volume  = {104},
number  = {3},
pages   = {733--738},
year    = {2007},
doi     = {10.1073/pnas.0605139104}
}


2006

1. Tail Ordering Due to Headgroup Hydrogen Bonding Interactions in Surfactant Monolayers at the Water−Oil Interface
Tikhonov AM, Patel H, Garde S and Schlossman ML, J. Phys. Chem. B ,110 (39) ,19093-19096 (2006)
Interactions between surfactants, and the resultant ordering of surfactant assemblies, can be tuned by the appropriate choice of head- and tailgroups. Detailed studies of the ordering of monolayers of long-chain n-alkanoic and n-alkanol monolayers at the water−vapor interface have demonstrated that rigid-rod all-trans ordering of the tailgroups is maintained upon replacing the alcohol with a carboxylic acid headgroup. In contrast, at the water−hexane liquid−liquid interface, we demonstrate that substitution of the −CH2OH with the −COOH headgroup produces a major conformational change of the tailgroup from disordered to ordered. This is demonstrated by the electron density profiles of triacontanol (CH3(CH2)29OH) and triacontanoic acid (CH3(CH2)28COOH) monolayers at the water−hexane interface, as determined by X-ray reflectivity measurements. Molecular dynamics simulations illustrate the presence of hydrogen bonding between the triacontanoic acid headgroups that is likely responsible for the tail ordering. A simple free energy illustrates the interplay between the attractive hydrogen bonding and the ordering of the tailgroup.
@article{tikhonov2006tail,
title   = {Tail ordering due to headgroup hydrogen bonding interactions in surfactant monolayers at the water-oil interface},
author  = {Tikhonov, Aleksey M and Patel, Harshit and Garde, Shekhar and Schlossman, Mark L},
journal = {The Journal of Physical Chemistry B},
volume  = {110},
number  = {39},
pages   = {19093--19096},
year    = {2006},
doi     = {10.1021/jp064120q}
}

2. Do Inverse Monte Carlo Algorithms Yield Thermodynamically Consistent Interaction Potentials?
Jain S, Garde S and Kumar SK, Ind. Eng. Chem. Res. ,45 (16) ,5614-5618 (2006)
We numerically verify a statistical mechanics theorem which shows that there is a one-to-one equivalence between the structure of a liquid (i.e., the pair correlation function) and its pairwise additive intermolecular potential. Specifically, we show for three systems interacting with simple spherically symmetric pairwise additive potentials that inverse Monte Carlo (IMC) simulations can obtain the underlying potentials by only using the target pair correlation functions. The convergence of potentials obtained by the standard IMC procedure is, however, extremely slow. Interestingly, we find that the repulsive part of the potential converges rapidly, consistent with the well-accepted notion that it essentially determines the structure of condensed liquids. We show that additional information about the system, such as thermodynamic properties (e.g., average energy and or pressure) can be included in a modified IMC procedure. Because internal energy and pressure are primarily sensitive to the attractive part of the potential, the convergence to the true potential is improved by an order of magnitude. Although the improved convergence is a technical advance, no new information is obtained on the final converged potential by this approach, as expected by the Henderson theorem.
@article{jain2006inverse,
title   = {Do inverse Monte Carlo algorithms yield thermodynamically consistent interaction potentials?},
author  = {Jain, Sandeep and Garde, Shekhar and Kumar, Sanat K},
journal = {Industrial \& engineering chemistry research},
volume  = {45},
number  = {16},
pages   = {5614--5618},
year    = {2006},
doi     = {10.1021/ie060042h}
}

3. Quantifying the protein core flexibility through analysis of cavity formation
Pereira B, Jain S and Garde S, J. Chem. Phys. ,124 ,074704 (2006)
We present an extensive analysis of cavity statistics in the interior of three different proteins, in liquid n-hexane, and in water performed using molecular-dynamics simulations. The heterogeneity of packing density over atomic length scales in different parts of proteins is evident in the wide range of values observed for the average cavity size, the probability of cavity formation, and the corresponding free energy of hard-sphere insertion. More interestingly, however, the distribution of cavity sizes observed at various points in the protein interior is surprisingly homogeneous in width. That width is significantly smaller than that measured for similar distributions in liquid n-hexane or water, indicating that protein interior is much less flexible than liquid hexane. The width of the cavity size distribution correlates well with the experimental isothermal compressibility data for liquids and proteins. An analysis of cavity statistics thus provides an efficient method to quantify local properties, such as packing, stiffness, or compressibility in heterogeneous condensed media.
@article{pereira2006quantifying,
title   = {Quantifying the protein core flexibility through analysis of cavity formation},
author  = {Pereira, Brian and Jain, Sandeep and Garde, Shekhar},
journal = {The Journal of chemical physics},
volume  = {124},
pages   = {074704},
year    = {2006},
doi     = {10.1063/1.2149848}
}

4. Detailed molecular simulations to investigate multicomponent diffusion models
Patel HA, Garde S and Nauman EB, AIChE J ,52 (4) ,1304-1307 (2006)
The theoretical treatment of multicomponent diffusion is complicated by the generally unknown dependence of diffusivities on the local concentration of species. As pointed out by Nauman and Savoca in 2001, the standard treatment uses an n-1 by n-1 matrix of diffusion coefficients for an n-component system and can give anomalous and non-physical results when there is no dominant component and when the various components have significantly different diffusivities. Although theoretically resolved by postulating diffusivities with suitable concentration dependence, there has been no practical resolution of this problem short of unrealistic, exhaustive experimentation. Nauman and Savoca proposed two models for multicomponent diffusion that produce only physically possible results, but they were unable to suggest which model was better. This article reports on molecular dynamic experiments that were designed to differentiate between the models. Specifically studied were ternary, liquid mixtures of ethane, octane, and hexadecane. It was found that the proportional flux model agrees with the molecular simulations. No cross-diffusion was observed in agreement with this model and in contrast to the alternative, pair-wise flux model. The proportional flux model is easy to implement and requires a minimum of data, although detailed, compositional dependent diffusion coefficients can be incorporated into the model when such data are available
@article{patel2006detailed,
title   = {Detailed molecular simulations to investigate multicomponent diffusion models},
author  = {Patel, Harshit A and Garde, Shekhar and Nauman, E Bruce},
journal = {AIChE journal},
volume  = {52},
number  = {4},
pages   = {1304--1307},
year    = {2006},
doi     = {10.1002/aic.10745}
}


2005

1. Direct determination of phase behavior of square-well fluids
Liu H, Garde S and Kumar SK, J. Chem. Phys. ,123 ,174505 (2005)
We have combined Gibbs ensemble Monte Carlo simulations with the aggregation volume-biased method in conjunction with the Gibbs-Duhem method to provide the first direct estimates for the vapor-solid, vapor-liquid, and liquid-solid phase coexistences of square-well fluids with three different ranges of attraction. Our results are consistent with the previous simulations and verify the notion that the vapor-liquid coexistence behavior becomes metastable for cases where the attraction well becomes smaller than 1.25 times the particle diameter. In these cases no triple point is found.
@article{liu2005direct,
title   = {Direct determination of phase behavior of square-well fluids},
author  = {Liu, Hongjun and Garde, Shekhar and Kumar, Sanat},
journal = {The Journal of chemical physics},
volume  = {123},
pages   = {174505},
year    = {2005},
doi     = {10.1063/1.2085051}
}

2. Thermal Resistance of Nanoscopic Liquid−Liquid Interfaces:  Dependence on Chemistry and Molecular Architecture
Patel HA, Garde S and Keblinski P, Nano Lett. ,5 (11) ,2225-2231 (2005)
Systems with nanoscopic features contain a high density of interfaces. Thermal transport in such systems can be governed by the resistance to heat transfer, the Kapitza resistance (RK), at the interface. Although soft interfaces, such as those between immiscible liquids or between a biomolecule and solvent, are ubiquitous, few studies of thermal transport at such interfaces have been reported. Here we characterize the interfacial conductance, 1/RK, of soft interfaces as a function of molecular architecture, chemistry, and the strength of cross-interfacial intermolecular interactions through detailed molecular dynamics simulations. The conductance of various interfaces studied here, for example, water−organic liquid, water−surfactant, surfactant−organic liquid, is relatively high (in the range of 65−370 MW/m2 K) compared to that for solid−liquid interfaces (10 MW/m2 K). Interestingly, the dependence of interfacial conductance on the chemistry and molecular architecture cannot be explained solely in terms of either bulk property mismatch or the strength of intermolecular attraction between the two phases. The observed trends can be attributed to a combination of strong cross-interface intermolecular interactions and good thermal coupling via soft vibration modes present at liquid−liquid interfaces.
@article{patel2005thermal,
title   = {Thermal resistance of nanoscopic liquid-liquid interfaces: Dependence on chemistry and molecular architecture},
author  = {Patel, Harshit A and Garde, Shekhar and Keblinski, Pawel},
journal = {Nano letters},
volume  = {5},
number  = {11},
pages   = {2225--2231},
year    = {2005},
doi     = {10.1021/nl051526q}
}

3. Hydrophobic hydration from small to large lengthscales: Understanding and manipulating the crossover
Rajamani S, Truskett TM and Garde S, Proc. Natl. Acad. Sci. USA ,102 (27) ,9475-9480 (2005)
Small and large hydrophobic solutes exhibit remarkably different hydration thermodynamics. Small solutes are accommodated in water with minor perturbations to water structure, and their hydration is captured accurately by theories that describe density fluctuations in pure water. In contrast, hydration of large solutes is accompanied by dewetting of their surfaces and requires a macroscopic thermodynamic description. A unified theoretical description of these lengthscale dependencies was presented by Lum, Chandler, and Weeks [(1999) J. Phys. Chem. B 103, 4570–4577]. Here, we use molecular simulations to study lengthscale-dependent hydrophobic hydration under various thermodynamic conditions. We show that the hydration of small and large solutes displays disparate dependencies on thermodynamic variables, including pressure, temperature, and additive concentration. Understanding these dependencies allows manipulation of the small-to-large crossover lengthscale, which is nanoscopic under ambient conditions. Specifically, applying hydrostatic tension or adding ethanol decreases the crossover length to molecular sizes, making it accessible to atomistic simulations. With detailed temperature-dependent studies, we further demonstrate that hydration thermodynamics changes gradually from entropic to enthalpic near the crossover. The nanoscopic lengthscale of the crossover and its sensitivity to thermodynamic variables imply that quantitative modeling of biomolecular self-assembly in aqueous solutions requires elements of both molecular and macroscopic hydration physics. We also show that the small-to-large crossover is directly related to the Egelstaff-Widom lengthscale, the product of surface tension and isothermal compressibility, which is another fundamental lengthscale in liquids.
@article{rajamani2005hydrophobic,
title   = {Hydrophobic hydration from small to large lengthscales: Understanding and manipulating the crossover},
author  = {Rajamani, Sowmianarayanan and Truskett, Thomas M and Garde, Shekhar},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume  = {102},
number  = {27},
pages   = {9475--9480},
year    = {2005},
doi     = {10.1073/pnas.0504089102}
}

4. Osmolyte Trimethylamine-N-Oxide Does Not Affect the Strength of Hydrophobic Interactions: Origin of Osmolyte Compatibility
Athawale MV, Dordick JS and Garde S, Biophysical J. ,89 (2) ,858-866 (2005)
Osmolytes are small organic solutes accumulated at high concentrations by cells/tissues in response to osmotic stress. Osmolytes increase thermodynamic stability of folded proteins and provide protection against denaturing stresses. The mechanism of osmolyte compatibility and osmolyte-induced stability has, therefore, attracted considerable attention in recent years. However, to our knowledge, no quantitative study of osmolyte effects on the strength of hydrophobic interactions has been reported. Here, we present a detailed molecular dynamics simulation study of the effect of the osmolyte trimethylamine-N-oxide (TMAO) on hydrophobic phenomena at molecular and nanoscopic length scales. Specifically, we investigate the effects of TMAO on the thermodynamics of hydrophobic hydration and interactions of small solutes as well as on the folding-unfolding conformational equilibrium of a hydrophobic polymer in water. The major conclusion of our study is that TMAO has almost no effect either on the thermodynamics of hydration of small nonpolar solutes or on the hydrophobic interactions at the pair and many-body level. We propose that this neutrality of TMAO toward hydrophobic interactions—one of the primary driving forces in protein folding—is at least partially responsible for making TMAO a “compatible” osmolyte. That is, TMAO can be tolerated at high concentrations in organisms without affecting nonspecific hydrophobic effects. Our study implies that protein stabilization by TMAO occurs through other mechanisms, such as unfavorable water-mediated interaction of TMAO with the protein backbone, as suggested by recent experimental studies. We complement the above calculations with analysis of TMAO hydration and changes in water structure in the presence of TMAO molecules. TMAO is an amphiphilic molecule containing both hydrophobic and hydrophilic parts. The precise balance of the effects of hydrophobic and hydrophilic segments of the molecule appears to explain the virtual noneffect of TMAO on the strength of hydrophobic interactions.
@article{athawale2005osmolyte,
title   = {Osmolyte Trimethylamine-< i> N-Oxide Does Not Affect the Strength of Hydrophobic Interactions: Origin of Osmolyte Compatibility},
author  = {Athawale, Manoj V and Dordick, Jonathan S and Garde, Shekhar},
journal = {Biophysical journal},
volume  = {89},
number  = {2},
pages   = {858--866},
year    = {2005},
doi     = {10.1529/biophysj.104.056671}
}

5. Mesoscale model of polymer melt structure: Self-consistent mapping of molecular correlations to coarse-grained potentials
Ashbaugh HS, Patel HA, Kumar SK and Garde S, J. Chem. Phys. ,122 ,104908 (2005)
Development and application of coarse-graining methods to condensed phases of macromolecules is an active area of research. Multiscale modeling of polymeric systems using coarse-graining methods presents unique challenges. Here we apply a coarse-graining method that self-consistently maps structuralcorrelations from detailed molecular dynamics (MD) simulations of alkane oligomers onto coarse-grained potentials using a combination of MD and inverse Monte Carlo methods. Once derived, the coarse-grained potentials allow computationally efficient sampling of ensemble of conformations of significantly longer polyethylene chains. Conformationalproperties derived from coarse-grained simulations are in excellent agreement with experiments. The level of coarse graining provides a control over the balance of computational efficiency and retention of chemical identity of the underlying polymeric system. Challenges to extension and application of this and similar structure-based coarse-graining methods to model dynamics and phase behavior in polymeric systems are briefly discussed
@article{ashbaugh2005mesoscale,
title   = {Mesoscale model of polymer melt structure: Self-consistent mapping of molecular correlations to coarse-grained potentials},
author  = {Ashbaugh, Henry S and Patel, Harshit A and Kumar, Sanat K and Garde, Shekhar},
journal = {The Journal of chemical physics},
volume  = {122},
pages   = {104908},
year    = {2005},
doi     = {10.1063/1.1861455}
}

6. Molecularium Explores the World of Materials
Garde S, Schadler LS and Siegel RW, MRS Bulletin ,30 (02) ,132-133 (2005)
@article{garde2005molecularium,
title   = {Molecularium Explores the World of Materials},
author  = {Garde, Shekhar and Schadler, Linda S and Siegel, Richard W},
journal = {MRS Bulletin},
volume  = {30},
number  = {02},
pages   = {132--133},
year    = {2005},
doi     = {10.1557/mrs2005.44}
}

7. On the Salt-Induced Stabilization of Pair and Many-body Hydrophobic Interactions
Ghosh T, Kalra A and Garde S, J. Phys. Chem. B ,109 (1) ,642-651 (2005)
Salting-out of hydrophobic solutes in aqueous salt solutions and their relevance to salt effects on biophysical phenomena are now well appreciated. Although salt effects on hydrophobic transfer have been well studied, to our knowledge, no quantitative molecular simulation study of salt-induced strengthening of hydrophobic interactions has yet been reported. Here we present quantitative characterization of salt-induced strengthening of hydrophobic interactions at the molecular and nanoscopic length scales through molecular dynamics simulations. Specifically, we quantify the effect of NaCl on the potential of mean force between molecular hydrophobic solutes (methanes) and on conformational equilibria of a 25-mer hydrophobic polymer that efficiently samples ensembles of compact and extended states in water. In both cases, we observe relative stabilization of compact conformations that is accompanied by a clear depletion of salt density (preferential exclusion) and a slight enhancement of water density (preferential hydration) in the solute vicinity. We show that the structural details of salt exclusion can be related to the salt-induced free energy changes using preferential interaction coefficients. We also test the applicability of surface-area-based models to describe the salt-induced free energy changes. These models provide a useful empirical description that can be used to predict the effects of salt on conformational equilibria of hydrophobic solutes. However, we find that the effective increase in the surface tension of the solute-aqueous solution interface depends on the type and concentration of salt as well as the length-scale (i.e., molecular vs nanoscopic) of the conformational change. These calculations underscore the utility of simulation studies to connect quantitatively structural details at the molecular level (described by preferential hydration/exclusion) to macroscopic solvation thermodynamics. The hydrophobic polymer also provides a useful model for studies of effect of thermodynamic variables (P, T, salt/additives) on many-body hydrophobic interactions at nanometer length scales.
@article{ghosh2005salt,
title   = {On the salt-induced stabilization of pair and many-body hydrophobic interactions},
author  = {Ghosh, Tuhin and Kalra, Amrit and Garde, Shekhar},
journal = {The Journal of Physical Chemistry B},
volume  = {109},
number  = {1},
pages   = {642--651},
year    = {2005},
doi     = {10.1021/jp0475638}
}


2004

1. Hydration of Enzyme in Nonaqueous Media Is Consistent with Solvent Dependence of Its Activity
Yang L, Dordick JS, and Garde S, Biophys. J. ,87 (2) ,812-821 (2004)
Water plays an important role in enzyme structure and function in aqueous media. That role becomes even more important when one focuses on enzymes in low water media. Here we present results from molecular dynamics simulations of surfactant-solubilized subtilisin BPN' in three organic solvents (octane, tetrahydrofuran, and acetonitrile) and in pure water. Trajectories from simulations are analyzed with a focus on enzyme structure, flexibility, and the details of enzyme hydration. The overall enzyme and backbone structures, as well as individual residue flexibility, do not show significant differences between water and the three organic solvents over a timescale of several nanoseconds currently accessible to large-scale molecular dynamics simulations. The key factor that distinguishes molecular-level details in different media is the partitioning of hydration water between the enzyme and the bulk solvent. The enzyme surface and the active site region are well hydrated in aqueous medium, whereas with increasing polarity of the organic solvent (octane ? tetrahydrofuran ? acetonitrile) the hydration water is stripped from the enzyme surface. Water stripping is accompanied by the penetration of tetrahydrofuran and acetonitrile molecules into crevices on the enzyme surface and especially into the active site. More polar organic solvents (tetrahydrofuran and acetonitrile) replace mobile and weakly bound water molecules in the active site and leave primarily the tightly bound water in that region. In contrast, the lack of water stripping in octane allows efficient hydration of the active site uniformly by mobile and weakly bound water and some structural water similar to that in aqueous solution. These differences in the active site hydration are consistent with the inverse dependence of enzymatic activity on organic solvent polarity and indicate that the behavior of hydration water on the enzyme surface and in the active site is an important determinant of biological function especially in low water media.
@article{yang2004hydration,
title   = {Hydration of enzyme in nonaqueous media is consistent with solvent dependence of its activity},
author  = {Yang, Lu and Dordick, Jonathan S and Garde, Shekhar},
journal = {Biophys. J.},
volume  = {87},
number  = {2},
pages   = {812--821},
year    = {2004},
doi     = {10.1529/biophysj.104.041269}
}

2. Evaluation of selectivity changes in HIC systems using a preferential interaction based analysis
Xia F, Nagrath D, Garde S, and Cramer SM, Biotechnol. Bioeng. ,87 (3) ,354-363 (2004)
It is well established that salt enhances the interaction between solutes (e.g., proteins, displacers) and the weak hydrophobic ligands in hydrophobic interaction chromatography (HIC) and that various salts (e.g., kosmotropes, chaotropes, and neutral) have different effects on protein retention. In this article, the solute affinity in kosmotropic, chaotropic, and neutral mobile phases are compared and the selectivity of solutes in the presence of these salts is examined. Since solute binding in HIC systems is driven by the release of water molecules, the total number of released water molecules in the presence of various types of salts was calculated using the preferential interaction theory. Chromatographic retention times and selectivity reversals of both proteins and displacers were found to be consistent with the total number of released water molecules. Finally, the solute surface hydrophobicity was also found to have a significant effect on its retention in HIC systems.
@article{xia2004evaluation,
title   = {Evaluation of selectivity changes in HIC systems using a preferential interaction based analysis},
author  = {Xia, Fang and Nagrath, Deepak and Garde, Shekhar and Cramer, Steven M},
journal = {Biotechnol. Bioeng.},
volume  = {87},
number  = {3},
pages   = {354--363},
year    = {2004},
doi     = {10.1002/bit.20120}
}

3. Size dependent ion hydration, its asymmetry, and convergence to macroscopic behavior
Rajamani S, Ghosh T, and Garde S, J. Chem. Phys. ,120 (9) ,4457-4466 (2004)
The packing and orientation of water molecules in the vicinity of solutes strongly influence the solute hydration thermodynamics in aqueous solutions. Here we study the charge density dependent hydration of a broad range of spherical monovalent ionic solutes (with solute diameters from ~0.4 nm to 1.7 nm) through molecular dynamics simulations in the simple point charge model of water. Consistent with previous experimental and theoretical studies, we observe a distinct asymmetry in the structure and thermodynamics of hydration of ions. In particular, the free energy of hydration of negative ions is more favorable than that of positive ions of the same size. This asymmetry persists over the entire range of solute sizes and cannot be captured by a continuum description of the solvent. The favorable hydration of negative ions arises primarily from the asymmetric charge distribution in the water molecule itself, and is reflected in (i) a small positive electrostatic potential at the center of a neutral solute, and (ii) clear structural (packing and orientation) differences in the hydration shell of positive and negative ions. While the asymmetry arising from the positive potential can be quantified in a straightforward manner, that arising from the structural differences in the fully charged states is difficult to quantify. The structural differences are highest for the small ions and diminish with increasing ion size, converging to hydrophobiclike hydration structure for the largest ions studied here. We discuss semiempirical measures following Latimer, Pitzer, and Slansky [J. Chem. Phys. 7, 108 (1939)] that account for these structural differences through a shift in the ion radius. We find that these two contributions account completely for the asymmetry of hydration of positive and negative ions over the entire range of ion sizes studied here. We also present preliminary calculations of the dependence of ion hydration asymmetry on the choice of water model that demonstrate its sensitivity to the details of ion-water interactions.
@article{rajamani2004size,
title   = {Size dependent ion hydration, its asymmetry, and convergence to macroscopic behavior},
author  = {Rajamani, Sowmianarayanan and Ghosh, Tuhin and Garde, Shekhar},
journal = {J. Chem. Phys.},
volume  = {120},
number  = {9},
pages   = {4457-4466},
year    = {2004}
doi     = {10.1063/1.1644536}
}

4. Methane Partitioning and Transport in Hydrated Carbon Nanotubes
Kalra A, Hummer G, and Garde S, J. Phys. Chem. B ,108 (2) ,544-549 (2004)
The well defined shape and size of carbon nanotubes (CNTs) makes them attractive candidates for theoretical and experimental studies of various nanoscopic phenomena such as protection and confinement of molecular species as well as transport of molecules through their interior pores. Here we investigate solute partitioning and transport using molecular dynamics simulations of CNTs in mixtures of hydrophobic solutes and water. The hydrophobic pores of CNTs provide a favorable environment for partitioning of hydrophobic solutes. We find that the transfer of a methane molecule from aqueous solution into the CNT interior is favored by about 16 kJ/mol of free energy. In 50 molecular dynamics simulations, we observe that methane molecules replace water molecules initially inside the nanotubes, and completely fill their interior channels over a nanosecond time scale. Once filled with methane molecules, the nanotubes are able to transport methane from one end to the other through successive methane uptake and release events at the tube ends. We estimate a net rate of transport of about 11 methane molecules per nanotube and nanosecond for a 1 mol/L methane concentration gradient. This concentration-corrected rate of methane transport even exceeds that of water through nanotubes (1 per nanosecond at a 1 mol/L osmotic gradient). These results have implications for the design of molecule-selective CNT devices that may act through mechanisms similar to those of biological transmembrane channels.
@article{kalra2004methane,
title   = {Methane partitioning and transport in hydrated carbon nanotubes},
author  = {Kalra, Amrit and Hummer, Gerhard and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {108},
number  = {2},
pages   = {544--549},
year    = {2004},
doi     = {10.1021/jp035828x}
}


2003

1. Role of Backbone Hydration and Salt-Bridge Formation in Stability of a-Helix in Solution
Ghosh T, Garde S, and Garcia AE, Biophys. J. ,85 (5) ,3187-3193 (2003)
We test molecular level hypotheses for the high thermal stability of a-helical conformations of alanine-based peptides by performing detailed atomistic simulations of a 20-amino-acid peptide with explicit treatment of water. To assess the contribution of large side chains to a-helix stability through backbone desolvation and salt-bridge formation, we simulate the alanine-rich peptide, Ace-YAEAAKAAEAAKAAEAAKAF-Nme, referred to as the EK peptide, that has three pairs of (i, i+3) glutamic acid(-) and lysine(+) substitutions. Efficient configurational sampling of the EK peptide over a wide temperature range enabled by the replica exchange molecular dynamics technique allows characterization of the stability of a-helix with respect to heat-induced unfolding. We find that near ambient temperatures, the EK peptide predominately samples a-helical configurations with 80% fractional helicity at 300K. The helix melts over a broad range of temperatures with melting temperature, Tm, equal to 350K, that is significantly higher than the Tm of a 21-residue polyalanine peptide, A21. Salt-bridges between oppositely charged Glu- and Lys+ side chains can, in principle, provide thermal stability to a-helical conformers. For the specific EK peptide sequence, we observe infrequent formation of Glu-Lys salt-bridges (with ~ 10-20 % probability) and therefore we conclude that salt-bridge formation does not contribute significantly to the EK peptide's helical stability. However, lysine side chains are found to shield specific (i, i+4) backbone hydrogen bonds from water, indicating that large side-chain substituents can play an important role in stabilizing a-helical configurations of short peptides in aqueous solution through mediation of water access to backbone hydrogen bonds. These observations have implications on molecular engineering of peptides and biomolecules in the design of their thermostable variants where the shielding mechanism can act in concert with other factors such as salt-bridge formation, thereby increasing thermal stability considerably.
@article{ghosh2003role,
title   = {Role of Backbone Hydration and Salt-Bridge Formation in
Stability of< i> $\alpha$-Helix in Solution},
author  = {Ghosh, Tuhin and Garde, Shekhar and Garc{\'\i}a, Angel E},
journal = {Biophys. J.},
volume  = {85},
number  = {5},
pages   = {3187--3193},
year    = {2003},
doi     = {10.1016/S0006-3495(03)74736-5}
}

2. Molecular structure and hydrophobic solvation thermodynamics at an octane-water interface
Patel HA, Nauman EB, and Garde S, J. Chem. Phys. ,119 (17) ,9199-9206 (2003)
We present results from atomically detailed molecular dynamics simulation of an octane-water liquid-liquid interface. We specifically focus on water structure, orientation, coordination numbers, and hydrogen bonding at the interface. In addition, we probe the interface through insertions of different nonpolar solutes at various locations in the system. Several interesting details of the interface emerge from our calculations. We find that the number density profiles of both water and octane vary monotonically through the interface in a sigmoidal fashion over approximately 1 nm 1-99 interfacial width. Interestingly, the overall heavy-atom density profile shows a distinct minimum in the interfacial region that reflects the hydrophobic nature of the hydration at the octane-water interface. Furthermore, calculations of excess chemical potentials of attractive Lennard-Jones and purely repulsive hydrophobic solutes display an interfacial minimum, indicating the relative ease of cavity formation at the interface. The inhomogeneous nature of the interface affects the water structure and hydrogen-bonding properties at the interface. We find that water coordination number as well as the number of hydrogen bonds water molecules make with their neighbors decreases through the interface as we move from bulk water to the octane phase. As a result, we find populations of water with low coordination numbers, including monomeric water species in the interfacial region. Although the number of hydrogen bonds per water is low in the interfacial region, a larger fraction of coordination waters is hydrogen bonded to the central water in the interfacial region.
@article{patel2003molecular,
title   = {Molecular structure and hydrophobic solvation thermodynamics at an octane--water interface},
author  = {Patel, Harshit A and Nauman, E Bruce and Garde, Shekhar},
journal = {The Journal of chemical physics},
volume  = {119},
number  = {17},
pages   = {9199--9206},
year    = {2003}
doi     = {10.1063/1.1605942}
}

3. Osmotic water transport through carbon nanotube membranes
Kalra A, Garde S, and Hummer G, Proc. Natl. Acad. Sci. ,100 (8) ,10175-10180 (2003)
We use molecular dynamics simulations to study osmotically driven transport of water molecules through hexagonally packed carbon nanotube membranes. Our simulation setup comprises two such semipermeable membranes separating compartments of pure water and salt solution. The osmotic force drives water flow from the pure-water to the salt-solution compartment. Monitoring the flow at molecular resolution reveals several distinct features of nanoscale flows. In particular, thermal fluctuations become significant at the nanoscopic length scales, and as a result, the flow is stochastic in nature. Further, the flow appears frictionless and is limited primarily by the barriers at the entry and exit of the nanotube pore. The observed flow rates are high (5.8 water molecules per nanosecond and nanotube), comparable to those through the transmembrane protein aquaporin-1, and are practically independent of the length of the nanotube, in contrast to predictions of macroscopic hydrodynamics. All of these distinct characteristics of nanoscopic water flow can be modeled quantitatively by a 1D continuous-time random walk. At long times, the pure-water compartment is drained, and the net flow of water is interrupted by the formation of structured solvation layers of water sandwiched between two nanotube membranes. Structural and thermodynamic aspects of confined water monolayers are studied.
@article{kalra2003osmotic,
title   = {Osmotic water transport through carbon nanotube membranes},
author  = {Kalra, Amrit and Garde, Shekhar and Hummer, Gerhard},
journal = {Proc. Natl. Acad. Sci.},
volume  = {100},
number  = {18},
pages   = {10175--10180},
year    = {2003},
doi     = {10.1073/pnas.1633354100}
}

4. Helix propensities of short peptides: Molecular dynamics versus bioinformatics
Bystroff C and Garde S, Proteins ,50 (4) ,552-562 (2003)
Knowledge-based potential functions for protein structure prediction assume that the frequency of occurrence of a given structure or a contact in the protein database is a measure of its free energy. Here, we put this assumption to test by comparing the results obtained from sequence-structure cluster analysis with those obtained from long all-atom molecular dynamics simulations. Sixty-four eight-residue peptide sequences with varying degrees of similarity to the canonical sequence pattern for amphipathic helix were drawn from known protein structures, regardless of whether they were helical in the protein. Each was simulated using AMBER 6.0 for at least 10 ns using explicit waters. The total simulation time was 1176 ns. The resulting trajectories were tested for reproducibility, and the helical content was measured. Natural peptides whose sequences matched the amphipathic helix motif with greater than 50% confidence were significantly more likely to form helix during the course of the simulation than peptides with lower confidence scores. The sequence pattern derived from the simulation data closely resembles the motif pattern derived from the database cluster analysis. The difficulties encountered in sampling conformational space and sequence space simultaneously are discussed.
@article{bystroff2003helix,
title   = {Helix propensities of short peptides: molecular dynamics versus bioinformatics},
author  = {Bystroff, Christopher and Garde, Shekhar},
journal = {Proteins: Structure, Function, and Bioinformatics},
volume  = {50},
number  = {4},
pages   = {552--562},
year    = {2003},
doi     = {10.1002/prot.10252}
}

5. Water-Mediated Three-Particle Interactions between Hydrophobic Solutes:? Size, Pressure, and Salt Effects
Ghosh T, Garcia AE, and Garde S, J. Phys. Chem. B ,107 (2) ,612-617 (2003)
We use molecular dynamics (MD) simulations of solutions of hydrophobic solutes in explicit water to study the many-body character of hydrophobic interactions at the level of solute-solute-solute three-particle correlations. Comparisons of the calculated three-particle potentials of mean force (PMF) with that obtained by adding solute-solute pair PMFs are used to quantify the many-body effect. Our results shed light on both the range and magnitude of many-body (i.e., nonadditivity) effects. We find that the nonadditivity effects depend on the specific configuration of the three interacting particles and are short-ranged, restricted primarily to locations of the third solute within the first two solvation shells of the primary solute pair. The contact and solvent-separated configurations show anticooperative behavior (i.e., the actual three-particle PMF is less favorable than the pairwise additive approximation), whereas cooperativity is observed at the desolvation barrier. Increasing the solute size makes the nonadditive effects uniformly more anticooperative. Nonadditivity behavior is also short-ranged at higher pressures and in NaCl solutions. Interestingly, increasing pressure changes the nonadditivity effects toward cooperativity, whereas the opposite is true upon the addition of salt to the solution. The implications of these results on more complex self-assembly processes are discussed.
@article{ghosh2003water,
title   = {Water-mediated three-particle interactions between hydrophobic solutes: size, pressure, and salt effects},
author  = {Ghosh, Tuhin and Garc{\'\i}a, Angel E and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {107},
number  = {2},
pages   = {612--617},
year    = {2003},
doi     = {10.1021/jp0220175}
}


2002

1. Molecular dynamics simulation of C8E5 micelle in explicit water: structure and hydrophobic solvation thermodynamics
Garde S, Yang L, Dordick JS, and Paulaitis ME, Mol. Phys. ,100 (14) ,2299-2306 (2002)
Results are presented from a large scale molecular dynamics (MD) simulation of a non-ionic micelle comprising 80 C8E5 surfactant molecules in 9798 explicit TIP3P waters. The results are consistent with the conventional static picture of a simple spherical micelle ("hydrophilic heads out, hydrophobic tails in"). In addition, the MD simulation reveals structural details that show clearly the dynamic nature of the micellar aggregate. The micelle is roughly spherical with thermal fluctuations leading to instantaneous shapes that are significantly non-spherical. The individual surfactant molecules adopt various nonlinear conformations, predominately in the hydrophilic segment, thereby leading to the overall compact globular shape of the micelle aggregate. Atomic distribution functions and dihedral angle distributions show that the micelle interior is similar to liquid n-octane. Although no water penetration in the micelle hydrophobic core is observed, there is considerable exposure of the hydrophobic tails of the surfactant molecules to water in the interfacial region. The excess chemical potentials of hydrophobic Lennard-Jones (LJ) solutes and their WCA analogs show a preference for the michelle core relative to bulk water. Interestingly, the solvation energies of LJ solutes show a minimum in the interfacial region. A qualitative explanation for this behaviour based on different packing tendencies of water and chain-like molecules is presented.
@article{garde2002molecular,
title   = {Molecular dynamics simulation of C8E5 micelle in explicit water: structure and hydrophobic solvation thermodynamics},
author  = {Garde, Shekhar and Yang, Lu and Dordick, Jonathan S and Paulaitis, Michael E},
journal = {Mol. Phys.},
volume  = {100},
number  = {14},
pages   = {2299--2306},
year    = {2002},
doi     = {10.1080/00268970110118312}
}

2. Enthalpy and entropy contributions to the pressure dependence of hydrophobic interactions
Ghosh T, Garcia AE, and Garde S, J. Chem. Phys. ,116 (6) ,2480-2486 (2002)
We use long molecular dynamics simulations of methane molecules in explicit water at three different temperatures at pressures of 1 and 4000 atm to calculate entropic and enthalpic contributions to the free energy of methane-methane association. In agreement with previous simulation studies, we find that the contact minimum is dominated by entropy whereas the solvent-separated minimum is stabilized by favorable enthalpy of association. Both the entropy and enthalpy at the contact minimum change negligibly with increasing pressure leading to the relative pressure insensitivity of the contact minimum configurations. In contrast, we find that the solvent-separated configurations are increasingly stabilized at higher pressures by enthalpic contributions that prevail over the slightly unfavorable entropic contributions to the free energy. The desolvation barrier is dominated by unfavorable enthalpy of maintaining a dry volume between methanes. However, the increasing height of the desolvation barrier with increasing pressures results from entropy changes at the barrier configurations. Further resolution of the enthalpy of association shows that major contributions to the enthalpy arise from changes in water-water interactions and the mechanical work(P?V) expended in bringing the methanes to a separation of r. A connection of these thermodynamic features with the underlying changes in water structure is made by calculating methane-methane-water oxygen triplet correlation functions.
@article{ghosh2002enthalpy,
title   = {Enthalpy and entropy contributions to the pressure dependence of hydrophobic interactions},
author  = {Ghosh, Tuhin and Garc{\'\i}a, Angel E and Garde, Shekhar},
journal = {J. Chem. Phys.},
volume  = {116},
number  = {6},
pages   = {2480--2486},
year    = {2002},
doi     = {10.1063/1.1431582}
}


2001

1. Effect of Chain Length on Microscopic Density Fluctuations and Solvation in Polymeric Fluids
Garde S, Hummer G and Khare R, Polymeric Materials: Science and Engineering ,85 ,449 (2001)
@article{garde2001effect,
title   = {Effect of Chain Length on Microscopic Density Fluctuations and Solvation in Polymeric Fluids},
author  = {Garde, Shekhar and Hummer, Gerhard and Khare, Rajesh},
journal = {Polymeric Materials: Science and Engineering},
volume  = {85},
pages   = {449},
year    = {2001},
}

2. Molecular dynamics simulations of pressure effects on hydrophobic interactions
Ghosh T, Garcia AE and Garde S, J. Am. Chem. Soc. ,123 (44) ,10997-11003 (2001)
We report results on the pressure effects on hydrophobic interactions obtained from molecular dynamics simulations of aqueous solutions of methanes in water. A wide range of pressures that is relevant to pressure denaturation of proteins is investigated. The characteristic features of water-mediated interactions between hydrophobic solutes are found to be pressure-dependent. In particular, with increasing pressure we find that (1) the solvent-separated configurations in the solute-solute potential of mean force (PMF) are stabilized with respect to the contact configurations; (2) the desolvation barrier increases monotonically with respect to both contact and solvent-separated configurations; (3) the locations of the minima and the barrier move toward shorter separations; and (4) pressure effects are considerably amplified for larger hydrophobic solutes. Together, these observations lend strong support to the picture of the pressure denaturation process proposed previously by Hummer et al. (Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 1552):? with increasing pressure, the transfer of water into protein interior becomes key to the pressure denaturation process, leading to the dissociation of close hydrophobic contacts and subsequent swelling of the hydrophobic protein interior through insertions of water molecules. The pressure dependence of the PMF between larger hydrophobic solutes shows that pressure effects on the interaction between hydrophobic amino acids may be considerably amplified compared to those on the methane-methane PMF.
@article{ghosh2001molecular,
title   = {Molecular dynamics simulations of pressure effects on hydrophobic interactions},
author  = {Ghosh, Tuhin and Garc{\'\i}a, Angel E and Garde, Shekhar},
journal = {J. Am. Chem. Soc.},
volume  = {123},
number  = {44},
pages   = {10997--11003},
year    = {2001},
doi     = {10.1021/ja010446v}
}

3. Temperature dependence of hydrophobic hydration and entropy convergence in an isotropic model of water
Garde S and Ashbaugh HS, J. Chem. Phys. ,115 (2) ,977 (2001)
We have investigated temperature dependence of hydrophobic hydration and molecular-scale density fluctuations in an isotropic single-site model of water originally devised by Head-Gordon and Stillinger [J. Chem. Phys. 98, 3313 (1993)] using Monte Carlo simulations. Our isotropic model of water, HGS water, has the same oxygen--oxygen radial distribution function as that of the simple point charge (SPC) water at room temperature and water density. For HGS water, we find that non-Gaussian occupancy fluctuations lead to cavity formation probabilities that are considerably lower than in SPC water. Wetting of a hard-sphere solute by HGS water is also found to be significantly greater than that by SPC water. These observations can be understood in terms of differences in Hamiltonians of the two water models. Despite these differences in the details of hydration, small hydrophobic solutes display many of the well-known thermodynamic finger prints of hydrophobic hydration once the variation of density with temperature, ?(T), along the saturation curve of real liquid water is followed for HGS water. For the hydration of small solutes, the entropy convergence is observed at temperatures of 400. These observations emphasize that the phase behavior of liquid water contains crucial information regarding thermodynamics of solvation phenomena.
@article{garde2001temperature,
title   = {Temperature dependence of hydrophobic hydration and entropy convergence in an isotropic model of water},
author  = {Garde, Shekhar and Ashbaugh, Henry S},
journal = {J. Chem. Phys.},
volume  = {115},
number  = {2},
pages   = {977},
year    = {2001},
doi     = {10.1063/1.1379576}
}

4. Salting-in and salting-out of hydrophobic solutes in aqueous salt solutions
Kalra A, Tugcu N, Cramer SM and Garde S, J. Phys. Chem. B ,105 (27) ,6380-6386 (2001)
We present results on the thermodynamic and structural aspects of the hydration of hydrophobic solutes in three tetramethylammonium [N(CH3)4+] salt solutions at various concentrations obtained from molecular dynamics simulations. Monovalent counterions of different sizesF-, Cl-, and a relatively large model ion BI-are chosen in order to cover a range of kosmotropic to chaotropic behaviors. Chemical potentials of hard-sphere solutes obtained using test particle insertions display both salting-in and salting-out effects depending on the type of salt. Water and salt-ion densities in the vicinity of hard-sphere solutes are calculated. Small and strongly hydrated F- ions (kosmotropes) are excluded from the vicinity of hydrophobic solutes, leading to an increase in local water densities near hydrophobic solutes (i.e., preferential hydration). This increases the excess chemical potential of hydrophobic solutes in solution which leads to salting-out. Opposite behavior is observed for large, less favorably hydrated BI- ions (chaotropes) which associate strongly with hydrophobic solutes. Compressive forces due to neighboring water molecules, cations, and anions on the surface of the hard sphere solute are calculated. We find that water molecules make the most significant contribution toward the total compressive force. This explains the observed linear correlation between the extent of preferential hydration or dehydration of the solute surface and salting-out or salting-in effects. The trends in the thermodynamics of hydration of hydrophobic solutes upon addition of salts are explained in terms of the structural hydration of individual salt ions.
@article{kalra2001salting,
title   = {Salting-in and salting-out of hydrophobic solutes in aqueous salt solutions},
author  = {Kalra, Amrit and Tugcu, Nihal and Cramer, Steven M and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {105},
number  = {27},
pages   = {6380--6386},
year    = {2001},
doi     = {10.1021/jp010568+}
}

5. Helix nucleation kinetics from molecular simulations in explicit solvent
Hummer G, Garcia, AE and Garde S, Proteins: Structure, Function, and Bioinformatics ,42 (1) ,77-84 (2001)
We study the reversible folding/unfolding of short Ala and Gly-based peptides by molecular dynamics simulations of all-atom models in explicit water solvent. A kinetic analysis shows that the formation of a first a-helical turn occurs within 0.1--1 ns, in agreement with the analyses of laser temperature jump experiments. The unfolding times exhibit Arrhenius temperature dependence. For a rapidly nucleating all-Ala peptide, the helix nucleation time depends only weakly on temperature. For a peptide with enthalpically competing turn-like structures, helix nucleation exhibits an Arrhenius temperature dependence, corresponding to the unfolding of enthalpic traps in the coil ensemble. An analysis of structures in a transition-state ensemble shows that helix-to-coil transitions occur predominantly through breaking of hydrogen bonds at the helix ends, particularly at the C-terminus. The temperature dependence of the transition-state ensemble and the corresponding folding/unfolding pathways illustrate that folding mechanisms can change with temperature, possibly complicating the interpretation of high-temperature unfolding simulations. The timescale of helix formation is an essential factor in molecular models of protein folding. The rapid helix nucleation observed here suggests that transient helices form early in the folding event.
@article{hummer2001helix,
title   = {Helix nucleation kinetics from molecular simulations in explicit solvent},
author  = {Hummer, Gerhard and Garc\'\ia, Angel E. and Garde, Shekhar},
journal = {Proteins: Structure, Function, and Bioinformatics},
volume  = {42},
number  = {1},
pages   = {77--84},
year    = {2001},
doi     = {10.1002/1097-0134(20010101)42:1%3C77::AID-PROT80%3E3.0.CO;2-%23}
}


2000

1. Conformational Diffusion and Helix Formation Kinetics
Hummer G, Garcia, AE and Garde S, Phys. Rev. Lett. ,85 (12) ,2637-2640 (2000)
The time, temperature, and sequence dependences of helix formation kinetics of fully atomistic peptide models in explicit solvent are described quantitatively by a diffusive search within the coil state with barrierless transitions into the helical state. Conformational diffusion leads to nonexponential kinetics and jump-width dependences in temperature jump experiments.
@article{hummer2000conformational,
title   = {Conformational Diffusion and Helix Formation Kinetics},
author  = {Hummer, Gerhard and Garc\'\ia, Angel E. and Garde, Shekhar},
journal = {Phys. Rev. Lett.},
volume  = {85},
number  = {12},
pages   = {2637--2640},
year    = {2000},
doi     = {10.1103/PhysRevLett.85.2637}
}

2. New perspectives on hydrophobic effects
Hummer G, Garde S, Garcia AE and Pratt LR, Chem. Phys. ,258 (2) ,349-370 (2000)
Recent breakthroughs in the theory of hydrophobic effects permit new analyses of several characteristics of hydrophobic hydration and interaction. Heat capacities of non-polar solvation, and their temperature dependences, are analyzed within an information theory approach, using experimental information available from bulk liquid water. Non-polar solvation in aqueous electrolytes is studied by computer simulations, and interpreted within the information theory. We also study the preferential solvation of small non-polar molecules in heavy water (D2O) relative to light water (H2O) and find that this revealing difference can be explained by the higher compressibility of D2O. We develop a quasi-chemical description of hydrophobic hydration that incorporates the hydration structure and permits quantum-mechanical treatment of the solute. Finally, these new results are discussed in the context of hydrophobic effects in protein stability and folding, and of mesoscopic hydrophobic effects such as dewetting.
@article{hummer2000new,
title   = {New perspectives on hydrophobic effects},
author  = {Hummer, G and Garde, S and Garc{\i}a, AE and Pratt, LR},
journal = {Chem. Phys.},
volume  = {258},
number  = {2},
pages   = {349--370},
year    = {2000},
doi     = {10.1016/S0301-0104(00)00115-4}
}

3. Microscopic density fluctuations and solvation in polymeric fluids
Garde S, Khare R and Hummer G, J. Chem. Phys. ,112 (3) ,1574 (2000)
The information theory approach is used to study molecular-scale density fluctuations and solvation of hard-core molecules in a condensed polymeric system, supported by extensive computer simulations. In contrast to simple liquids, it is found that the bond connectivity in polymers leads to non-Gaussian density fluctuations in molecular volumes. We define renormalized polymers with a reduced number of monomers of increased effective size. This reduces correlations between monomers and simplifies the effective density fluctuations. Chemical potentials of hard-core solutes in polyethylene can then be calculated accurately using information theory.
@article{garde2000microscopic,
title   = {Microscopic density fluctuations and solvation in polymeric fluids},
author  = {Garde, Shekhar and Khare, Rajesh and Hummer, Gerhard},
journal = {J. Chem. Phys.},
volume  = {112},
number  = {3},
pages   = {1574},
year    = {2000},
doi     = {10.1063/1.480705}
}


1999

1. Theories of hydrophobic effects and the description of free volume in complex liquids
Pratt LR, Garde S and Hummer G, NATO Science Series: New Approaches to Problems in Liquid State Theory ,529 ,407-420 (1999)
Recent progress on molecular theories of hydration of nonpolar solutes in aqueous solution has led to new ways of thinking about the old issue of free, or available volume in liquids. This article surveys the principal new results with particular attention to general issues of packing in liquids.
@article{pratt1999theories,
title     = {Theories of hydrophobic effects and the description of free volume in complex liquids},
author    = {Pratt, Lawrence R. and Garde, Shekhar and Hummer, Gerhard},
booktitle = {New Approaches to Problems in Liquid State Theory},
series    = {NATO Science Series},
editor    = {Caccamo, Carlo and Hansen, Jean-Pierre and Stell, George},
volume    = {529},
pages     = {407--420},
year      = {1999},
doi       = {10.1007/978-94-011-4564-0_23}
}

2. Conformational equilibria of alkanes in aqueous solution: Relationship to water structure near hydrophobic solutes
Hummer G, Garde S, Garcia AE, Paulaitis ME and Pratt LR, Biophys. J. ,77 (2) ,645-654 (1999)
Conformational free energies of butane, pentane, and hexane in water are calculated from molecular simulations with explicit waters and from a simple molecular theory in which the local hydration structure is estimated based on a proximity approximation. This proximity approximation uses only the two nearest carbon atoms on the alkane to predict the local water density at a given point in space. Conformational free energies of hydration are subsequently calculated using a free energy perturbation method. Quantitative agreement is found between the free energies obtained from simulations and theory. Moreover, free energy calculations using this proximity approximation are approximately four orders of magnitude faster than those based on explicit water simulations. Our results demonstrate the accuracy and utility of the proximity approximation for predicting water structure as the basis for a quantitative description of n-alkane conformational equilibria in water. In addition, the proximity approximation provides a molecular foundation for extending predictions of water structure and hydration thermodynamic properties of simple hydrophobic solutes to larger clusters or assemblies of hydrophobic solutes.
@article{ashbaugh1999conformational,
title   = {Conformational equilibria of alkanes in aqueous solution: Relationship to water structure near hydrophobic solutes},
author  = {Ashbaugh, Henry S. and Garde, Shekhar and Hummer, Gerhard and Kaler, Eric W. and Paulaitis, Michael E.},
journal = {Biophys. J.},
volume  = {77},
number  = {2},
pages   = {645--654},
year    = {1999},
doi     = {10.1016/S0006-3495(99)76920-1}
}

3. Hydration of the tetramethylammonium ion: From water structure to the free energy of hydration
Garde S, Hummer G and Paulaitis ME, AIP Conf. Proc. ,492 ,202-224 (1999)
We focus on prediction of structural organization of water in the vicinity of molecular ions and relating this water structure quantitatively to the ion hydration free energy. Analogous to results for clusters comprising covalently bonded nonpolar sites, we found that water structure near tetramethylammonium (TMA) ions in various charge states can be predicted sufficiently accurately by using proximity approximation. In particular, we show that a modified two-site proximity approximation that uses pair and triplet correlations with three nearest ion sites is able to capture details of water structure including asymmetry of hydration of positive and negative ions. We integrate the predicted charge densities along with a background charge applied uniformly within the integration sphere to calculate electrostatic potentials at the charge sites. The background charge density is chosen such that Stillinger-Lovett zeroth moment sum rule is satisfied within the integration sphere. Hydration free energies of TMA ion in seven different charge states (-3e,-2e,+3e) calculated using electrostatic potentials are in excellent agreement with molecular simulation results using Ewald summation technique and reproduce accurately the favorable hydration of negative ions with respect to positive ions.
@article{garde1999hydration,
title   = {Hydration of the tetramethylammonium ion: From water structure to the free energy of hydration},
author  = {Garde, Shekhar and Hummer, Gerhard and Paulaitis, Michael E.},
journal = {AIP Conf. Proc.},
volume  = {492},
pages   = {202--224},
year    = {1999},
doi     = {10.1063/1.1301529}
}

4. Molecular realism in default models for information theories of hydrophobic effects
Gomez MA, Pratt LR, Hummer G and Garde S, J. Phys. Chem. B ,103 (18) ,3520-3523 (1999)
This letter considers several physical arguments about contributions to hydrophobic hydration of inert gases, constructs default models to test them within information theories, and gives information theory predictions using those default models with moment information drawn from simulation of liquid water. Tested physical features include packing or steric effects, the role of attractive forces that lower the solvent pressure, and the roughly tetrahedral coordination of water molecules in liquid water. Packing effects (hard-sphere default model) and packing effects plus attractive forces (Lennard-Jones default model) are ineffective in improving the prediction of hydrophobic hydration free energies of inert gases over the previously used flat default model. However, a conceptually simple cluster Poisson model that incorporates tetrahedral coordination structure in the default model is effective for these predictions. These results provide a partial rationalization of the remarkable performance of the flat default model with two moments in previous applications. The cluster Poisson default model thus will be the subject of further refinement.
@article{gomez1999molecular,
title   = {Molecular realism in default models for information theories of hydrophobic effects},
author  = {Gomez, M. A. and Pratt, Lawrence R. and Hummer, Gerhard and Garde, Shekhar},
journal = {J. Phys. Chem. B},
volume  = {103},
number  = {18},
pages   = {3520--3523},
year    = {1999},
doi     = {10.1021/jp990337r}
}

5. Temperature dependence of the solubility of non-polar gases in water
Garde S, Garcia AE, Pratt LR and Hummer G, Biophys. Chem. ,78 (1) ,21-32 (1999)
An explanation is provided for the experimentally observed temperature dependence of the solubility and the solubility minimum of non-polar gases in water. The influence of solute size and solute--water attractive interactions on the solubility minimum temperature is investigated. The transfer of a non-polar solute from the ideal gas into water is divided into two steps: formation of a cavity in water with the size and shape of the solute and insertion of the solute in this cavity which is equivalent to turning on' solute--water attractive interactions. This two step process divides the excess chemical potential of the non-polar solute in water into repulsive and attractive contributions, respectively. The reversible work for cavity formation is modeled using an information theory model of hydrophobic hydration. Attractive contributions are calculated by modeling the water structure in the vicinity of non-polar solutes. These models make a direct connection between microscopic quantities and macroscopic observables. Moreover, they provide an understanding of the peculiar temperature dependences of the hydration thermodynamics from properties of pure water; specifically, bulk water density and the water oxygen--oxygen radial distribution function.
@article{garde1999temperature,
title   = {Temperature dependence of the solubility of non-polar gases in water},
author  = {Garde, Shekhar and Garc{\i}´a, Angel E and Pratt, Lawrence R and Hummer, Gerhard},
journal = {Biophys. Chem.},
volume  = {78},
number  = {1},
pages   = {21--32},
year    = {1999},
doi     = {10.1016/S0301-4622(99)00018-6}
}


1998

1. Hydrophobic Effects on a Molecular Scale
Hummer G, Garde S, Garcia AE, Paulaitis ME and Pratt LR, J. Phys. Chem. B ,102 (51) ,10469-10482 (1998)
A theoretical approach is developed to quantify hydrophobic hydration and interactions on a molecular scale, with the goal of insight into the molecular origins of hydrophobic effects. The model is based on the fundamental relation between the probability for cavity formation in bulk water resulting from molecular-scale density fluctuations and the hydration free energy of the simplest hydrophobic solutes, hard particles. This probability is estimated using an information theory (IT) approach, incorporating experimentally available properties of bulk water:? the density and radial distribution function. The IT approach reproduces the simplest hydrophobic effects:? hydration of spherical nonpolar solutes, the potential of mean force (PMF) between methane molecules, and solvent contributions to the torsional equilibrium of butane. Applications of this approach to study temperature and pressure effects provide new insights into the thermodynamics and kinetics of protein folding. The IT model relates the hydrophobic-entropy convergence observed in protein unfolding experiments to the macroscopic isothermal compressibility of water. A novel explanation for pressure denaturation of proteins follows from an analysis of the pressure stability of hydrophobic aggregates, suggesting that water penetrates the hydrophobic core of proteins at high pressures. This resolves a long-standing puzzle, whether pressure denaturation contradicts the hydrophobic-core model of protein stability. Finally, issues of dewetting of molecularly large nonpolar solutes are discussed in the context of a recently developed perturbation theory approach.
@article{hummer1998hydrophobic,
title   = {Hydrophobic effects on a molecular scale},
author  = {Hummer, Gerhard and Garde, Shekhar and Garcia, AE and Paulaitis, Michael E and Pratt, Lawrence R},
journal = {J. Phys. Chem. B},
volume  = {102},
number  = {51},
pages   = {10469--10482},
year    = {1998},
doi     = {10.1021/jp982873+}
}

2. Free energy of hydration of a molecular ionic solute: Tetramethylammonium ion
Garde S, Hummer G and Paulaitis ME, J. Chem. Phys. ,108 (4) ,1552 (1998)
We have performed Monte Carlo simulations of the tetramethylammonium ion, hydrated by 256 simple point charge (SPC) water molecules, as a function of total charge on the ion. The total charge was varied between -3e to +3e at intervals of 1e, and was distributed equally on the four methyl sites on the ion. Derivatives of the free energy with respect to charge were related to the fluctuations in the ion--water interaction energies using a cumulant expansion. This derivative information for the different charge states was found to give an accurate description of the free energy of hydration. The calculated hydration free energies were also found to be only weakly dependent on system size and the method used for calculating the electrostatic interactions (Ewald summation or generalized reaction field), when finite system size corrections are applied. The quadratic charge dependence was obtained for the free energy of hydration for both positive and negative ions as expected from the Born model. The hydration is, however, asymmetric. Negative ions are more favorably hydrated compared to positive ions. We relate this asymmetry of hydration to water structure; that is, to differences in the water oxygen and water hydrogen density profiles surrounding positive and negative ions. Another manifestation of this asymmetry is seen in the positive electrostatic potential at the center of methyl sites in the uncharged state of the tetramethylammonium solute.
@article{garde1998free,
title   = {Free energy of hydration of a molecular ionic solute: Tetramethylammonium ion},
author  = {Garde, Shekhar and Hummer, Gerhard and Paulaitis, Michael E.},
journal = {J. Chem. Phys.},
volume  = {108},
number  = {4},
pages   = {1552},
year    = {1998},
doi     = {10.1063/1.475526}
}

3. Cavity Expulsion and Weak Dewetting of Hydrophobic Solutes in Water
Hummer G and Garde S, Phys. Rev. Lett. ,80 (19) ,4193-4196 (1998)
Perturbation theory is used to study the solvation of nonpolar molecules in water, supported by extensive computer simulations. Two contributions to the solvent-mediated solute-water interactions are identified: a cavity potential of mean force that transforms by a simple translation when the solute size changes, and a solute-size-independent cavity-expulsion potential. The latter results in weak dewetting of the solute-water interface that can explain the approximate area dependence of solvation free energies with apparent surface tensions similar to macroscopic values.
@article{hummer1998cavity,
title   = {Cavity expulsion and weak dewetting of hydrophobic solutes in water},
author  = {Hummer, Gerhard and Garde, Shekhar},
journal = {Phys. Rev. Lett.},
volume  = {80},
number  = {19},
pages   = {4193--4196},
year    = {1998},
doi     = {10.1103/PhysRevLett.80.4193}
}

4. Reply to Comment on "Electrostatic Potentials and Free Energies of Solvation of Polar and Charged Molecules"
Hummer, G, Pratt LR, Garcia AE, Garde S, Berne BJ and Rick SW, J. Phys. Chem. B ,102 (19) ,3841-3843 (1998)
@article{hummer1998reply,
title   = {Reply to comment on Electrostatic potentials and free energies of solvation of polar and charged molecules},
author  = {Hummer, Gerhard and Pratt, Lawrence R. and Garc{\'\i}a, Angel E. and Garde, Shekhar and Berne, Bruce J. and Rick, Steven W.},
journal = {J. Phys. Chem. B},
volume  = {102},
number  = {19},
pages   = {3841--3843},
year    = {1998},
doi     = {10.1021/jp980145g}
}

5. The pressure dependence of hydrophobic interactions is consistent with the observed pressure denaturation of proteins
Hummer G, Garde S, Garcia AE, Paulaitis ME and Pratt LR, Proc. Natl. Acad. Sci. ,95 (4) ,1552-1555 (1998)
Proteins can be denatured by pressures of a few hundred MPa. This finding apparently contradicts the most widely used model of protein stability, where the formation of a hydrophobic core drives protein folding. The pressure denaturation puzzle is resolved by focusing on the pressure-dependent transfer of water into the protein interior, in contrast to the transfer of nonpolar residues into water, the approach commonly taken in models of protein unfolding. Pressure denaturation of proteins can then be explained by the pressure destabilization of hydrophobic aggregates by using an information theory model of hydrophobic interactions. Pressure-denatured proteins, unlike heat-denatured proteins, retain a compact structure with water molecules penetrating their core. Activation volumes for hydrophobic contributions to protein folding and unfolding kinetics are positive. Clathrate hydrates are predicted to form by virtually the same mechanism that drives pressure denaturation of proteins.
@article{hummer1998pressure,
title   = {The pressure dependence of hydrophobic interactions is consistent with the observed pressure denaturation of proteins},
author  = {Hummer, Gerhard and Garde, Shekhar and Garc{\'\i}a, Angel E. and Paulaitis, Michael E. and Pratt, Lawrence R.},
journal = {Proc. Natl. Acad. Sci.},
volume  = {95},
number  = {4},
pages   = {1552--1555},
year    = {1998},
doi     = {10.1073/pnas.95.4.1552}
}


1996

1. Hydration of biological macromolecules: from small solutes to proteins and nucleic acids
Garde, S, Hummer G, Paulaitis ME and Garcia AE, MRS Proceedings ,463 (1) ,21-26 (1996)
We present a method that uses two- and three-particle correlation functions between solute atoms and water molecules to approximate the density profile of water surrounding biomolecules. The method is based on a potential of mean force expansion and uses X-ray crystallography, NMR, or modeling structural input information on the biomolecule. For small hydrophobic solutes, we have calculated entropies of hydration using the predicted water densities that are in good agreement with experimental results. We have also predicted the hydration of the catabolite activator protein-DNA complex. The method is extremely efficient and makes possible the study of hydration of large biomolecules within CPU minutes.
@article{garde1996hydration,
title   = {Hydration of biological macromolecules: from small solutes to
proteins and nucleic acids},
author  = {Garde, Shekhar and Hummer, Gerhard and Paulaitis, Michael E.
and Garcia, Angel E.},
journal = {MRS Proceedings},
volume  = {463},
number  = {1},
pages   = {21--26},
year    = {1996},
doi     = {10.1557/PROC-463-21}
}

2. Origin of entropy convergence in hydrophobic hydration and protein folding
Garde, S, Hummer G, Garcia AE, Paulaitis ME and Pratt LR, Phys. Rev. Lett. ,77 (24) ,4966-4968 (1996)
An information theory model is used to construct a molecular explanation why hydrophobic solvation entropies measured in calorimetry of protein unfolding converge at a common temperature. The entropy convergence follows from the weak temperature dependence of occupancy fluctuations for molecular-scale volumes in water. The macroscopic expression of the contrasting entropic behavior between water and common organic solvents is the relative temperature insensitivity of the water isothermal compressibility. The information theory model provides a quantitative description of small molecule hydration and predicts a negative entropy at convergence. Interpretations of entropic contributions to protein folding should account for this result.
@article{garde1996origin,
title   = {Origin of entropy convergence in hydrophobic hydration and
protein folding},
author  = {Garde, Shekhar and Hummer, Gerhard and Garc{\'\i}a, Angel E.
and Paulaitis, Michael E. and Pratt, Lawrence R.},
journal = {Phys. Rev. Lett.},
volume  = {77},
number  = {24},
pages   = {4966--4968},
year    = {1996},
doi     = {10.1103/PhysRevLett.77.4966}
}

3. An information theory model of hydrophobic interactions
Hummer G, Garde S, Garcia AE, Pohorille A and Pratt LR, Proc. Natl. Acad. Sci. ,93 (17) ,8951-8955 (1996)
A molecular model of poorly understood hydrophobic effects is heuristically developed using the methods of information theory. Because primitive hydrophobic effects can be tied to the probability of observing a molecular-sized cavity in the solvent, the probability distribution of the number of solvent centers in a cavity volume is modeled on the basis of the two moments available from the density and radial distribution of oxygen atoms in liquid water. The modeled distribution then yields the probability that no solvent centers are found in the cavity volume. This model is shown to account quantitatively for the central hydrophobic phenomena of cavity formation and association of inert gas solutes. The connection of information theory to statistical thermodynamics provides a basis for clarification of hydrophobic effects. The simplicity and flexibility of the approach suggest that it should permit applications to conformational equilibria of nonpolar solutes and hydrophobic residues in biopolymers.
@article{hummer1996information,
title   = {An information theory model of hydrophobic interactions},
author  = {Hummer, Gerhard and Garde, Shekhar and Garc{\'\i}a, Angel E. and Pohorille, Andrew and Pratt, Lawrence R.},
journal = {Proc. Natl. Acad. Sci.},
volume  = {93},
number  = {17},
pages   = {8951--8955},
year    = {1996},
doi     = {10.1073/pnas.93.17.8951}
}

4. The hydrophobic effect
Paulaitis ME, Garde S and Ashbaugh HS, Curr. Opin. Colloid Interface Sci. ,1 (3) ,376-383 (1996)
Computer simulation and theoretical studies have improved significantly our understanding of the connection between the structural organization of water surrounding hydrophobic solutes and anomalous thermodynamic behavior associated with the hydrophobic effect. Recent studies have yielded the quantitative temperature dependence of hydrophobic interactions and the dependence of hydration free energy on solute size and shape. The success of new proximity approximations, which assume that water organization is only locally sensitive to solute structure, has encouraged the study of the hydration of complex hydrophobic solutes.
@article{paulaitis1996hydrophobic,
title   = {The hydrophobic effect},
author  = {Paulaitis, Michael E. and Garde, Shekhar and Ashbaugh, Henry S.},
journal = {Curr. Opin. Colloid Interface Sci.},
volume  = {1},
number  = {3},
pages   = {376--383},
year    = {1996},
doi     = {10.1016/S1359-0294(96)80137-3}
}

5. Hydrophobic hydration: Inhomogeneous water structure near nonpolar molecular solutes
Garde S, Hummer G, Garcia AE, Pratt LR and Paulaitis ME, Phys. Rev. E ,53 (5) ,R4310-R4313 (1996)
A potential of mean force (PMF) expansion is used to predict the water structure near nonpolar solutes having different shapes and molecular conformations. The decomposition of n-particle PMFs into pair and triplet contributions describes well the hydration of those solutes consisting of nonbonded clusters, but not covalently bonded molecules. Alternative proximity approximations are devised based on the local dependence of the water structure on solute shape and excluded volume. Accurate predictions obtained using these proximity approximations demonstrate that water organization is only locally sensitive to structural details of nonpolar solutes.
@article{garde1996hydrophobic,
title   = {Hydrophobic hydration: Inhomogeneous water structure near nonpolar molecular solutes},
author  = {Garde, Shekhar and Hummer, Gerhard and Garc{\'\i}a, Angel E. and Pratt, Lawrence R. and Paulaitis, Michael E.},
journal = {Phys. Rev. E},
volume  = {53},
number  = {5},
pages   = {R4310--R4313},
year    = {1996},
doi     = {10.1103/PhysRevE.53.R4310}
}

6. Hydrophobic interactions: conformational equilibria and the association of non-polar molecules in water
Garde S, Hummer G and Paulaitis ME, Faraday Discuss. ,103 ,125-139 (1996)
Recently developed proximity approximations have been used to calculate inhomogeneous water density profiles around non-polar molecular solutes. Relative Helmholtz energies of hydrophobic hydration are calculated from these density profiles using two inherently different approaches: Helmholtz energy perturbation and a multiparticle correlation function expansion. Entropic contributions to the hydration Helmholtz energy are also calculated using the multiparticle correlation function expansion for the entropy truncated at the level of pair correlations. We show that the proximity approximations describe water structure around a tetramethylammonium ion in good agreement with neutron diffraction experiments, and provide an accurate description of water structure around simple alkanes and benzene as reflected in their entropies of hydration. Further, we reproduce two important features of hydrophobic interactions: a highly favoured contact minimum and a solvent separated minimum in the PMFs for methane--methane and neopentane--neopentane association in water. Our calculations also show that the more compact conformations of n-butane and n-pentane are favoured in water, as expected based on traditional ideas regarding hydrophobic interactions.
@article{garde1996hydrophobic,
title   = {Hydrophobic interactions: conformational equilibria and the association of non-polar molecules in water},
author  = {Garde, Shekhar and Hummer, Gerhard and Paulaitis, Michael E.},
journal = {Faraday Discuss.},
volume  = {103},
pages   = {125--139},
year    = {1996},
doi     = {10.1039/FD9960300125}
}


1994

1. The entropy of hydration of simple hydrophobic solutes
Paulaitis ME, Ashbaugh HS and Garde S, Biophys. Chem. ,51 (2) ,349-357 (1994)
Infinite-dilution partial molar entropies of solvation of simple, monatomic solutes in water are defined in terms of the entropy associated with (1) solute insertion at constant volume and at a fixed position in the solvent, and (2) expansion or contraction of the pure solvent to maintain constant pressure. A statistical mechanical expansion for the entropy of solution in terms of multiparticle correlation functions is applied to this definition to identify three intrinsic contributions to the hydration entropy - solute-solvent pair correlations, rearrangement of solvent in the vicinity of the solute molecule, and expansion or contraction of the pure solvent - which we evaluate for the inert gases in water at 25°C. For the smaller solutes, we find that the solvent reorganization and solvent expansion contributions offset one another such that the entropy of hydration is determined almost exclusively by solute-water pair correlations. The solute-water pair correlation entropy also prevails as the primary factor determining entropies of hydration for the larger solutes; however, solvent reorganization now makes a small, negative contribution to the entropy.
@article{paulaitis1994entropy,
title   = {The entropy of hydration of simple hydrophobic solutes},
author  = {Paulaitis, Michael E. and Ashbaugh, Henry S. and Garde, Shekhar},
journal = {Biophys. Chem.},
volume  = {51},
number  = {2},
pages   = {349--357},
year    = {1994},
doi     = {10.1016/0301-4622(94)00055-7}
}
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