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Pressure effects on proteins and on
biomolecular interactions: Pressure effects
on proteins have both fundamental as well as applied relevance. To
understand thermodynamic and structural aspects of pressure denaturation,
we are performing molecular simulation studies of protein Staph Nuclease
under various pressures. These studies are complemented by simulations/theoretical
investigations of pressure effects on hydrophobic interactions. |
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Non-aqueous enzymology:
Being able to make proteins stable and functional in non-aqueous media
has many applications including those in synthesis of functional biomaterials.
In collaboration with Prof. Jonathan
S. Dordick, we are performing large-scale molecular dynamics simulation
investigation of Surfactant solubilized enzyme Subtilisin BPN' in a variety
of organic media. Our calculations highlight the role of hydration
water in enzyme activity in organic media. |
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Peptide folding problem: Data-mining
and related Bioinformatics approaches point to strong preferences for centain
short sequences to fold into corresponding local structural motifs (see
the
I-sites library by Bystroff and Baker). The free energetic basis
for local structure formation is, however, poorly understood. To
obtain such physical basis, in collaboration with Prof. Bystroff,
we are performing atomically detailed simulations of several tens of peptides
for a given local structure motif. Clustering of peptide structures
and comparison with Bioinformatics approaches provides new insights. |
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Effect of salts, osmolytes, and denaturants
on protein stability and structure: In
addition to T and P effects, salt/osmolyte/cosolvent effects on protein
structure and stability are of interest in bioprocessing operations.
We are approaching this problem from both levels -- at the level of proteins
and at the level of fundamental interactions that stabilize folded proteins
(e.g., hydrophobic interactions). The large-scale simulations provide
structural aspects of proteins in a variety of environments, with complementary
thermodynamic information from aqueous solution simulations. |
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Information theory:
Molecular-scale occupancy fluctuations in water were found to be surprisingly
simple and could be modeled with only minimal structural information (density
and radial distribution function) (see Hummer et al. PNAS 1996).
Further applications of this approach to study temperature and pressure
effects on hydrophobic phenomena have provided new insights into protein
folding/unfolding thermodynamics. Currently, we are extending this
approach to study cavity formation phenomena in mixtures and salt solutions,
as well as in non-aqueous systems, such as polymers and other condensed
media. |
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Hydrophobic Interactions:
Water-mediated attractive interactions between hydrophobic solutes are
primary contributors to the thermodynamic stability of proteins and other
self-assembled aggregates. We are using statistical mechanical theories
as well as molecular simulations to understand T, P, and salt/cosolvent
effects on hydrophobic interactions. In these studies, particular
emphasis is placed on the role of water structure, contributions from entropy
and enthalpy to the free energy of hydrophobic interactions. |
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Statistical Mechanics of Confined Systems:
Open ended single walled carbon nanotubes are ideal model systems that
resemble in shape and size to the pores in biological macromolecules, such
as transmembrane ion channel proteins. We are interested in thermodynamics
and kinetics of hydration and small molecule partitioning and transport
through such confined systems. To this end, novel simulations techniques
are being explored in collaboration with Dr.
Gerhard Hummer at NIH. |
