| Research Overview
The general focus of the group is the study of the effects
of solvent and cosolvents on the structure and dynamics of biomolecules
in solution. Our main tool is molecular dynamics simulations which
are used to provide atomic level detail concerning the properties
of these molecules. In particular, we are attempting to: i) extend
the application of computer simulations to more physiologically relevant
conditions; ii) characterize the denatured state of proteins as produced
by different cosolvents (denaturants); and iii) to understand the
structure and folding of peptides and proteins in solution.
Improved force field parameters
By simulating the motion of molecules using a computer one can investigate
the interactions between molecules at the atomic level. This can provide
new and interesting data not available by experiment. Molecular dynamics
simulation can be applied to investigate many diverse phenomena. However,
a key to their success is a correct modeling of the interaction energy (or
force field) between molecules. We are currently attempting to improve the
parameters used in molecular dynamics simulations in an effort to provide
more accurate properties of a variety of systems. New force fields have been
developed for mixtures of water with urea, acetone, sodium chloride, methanol,
and guanidium chloride, and are now being extended to cover other salts,
amides and alcohols.
Peptide folding
Using simulations we have been studying the mechanism by which peptides fold
to adopt stable structures in solution. This is an important aspect of the
much larger protein folding problem, which is the next step in discovering
the secrets unveiled by the Human Genome Project. Our current studies have
focused on the formation of hairpins. Using computer simulations we have
been able to observe hairpin formation and are now investigating the factors
that stabilize the final hairpin structure, and the role of the unfolded
state in hairpin stability.
Opioid peptides and delta-opioid receptor modeling
Opioids are small peptides that play a major role in our response to pain.
The design of improved and non addictive new pain killing drugs depends on
an understanding of the interaction between opioids and their receptor. The
exact site of opioid peptide binding to the receptor is unknown. We have
recently developed a model for the delta-opioid receptor which can be used
to probe the interactions between potential drug molecules and the receptor.
Model of the delta-opioid receptor in a lipid bilayer.
Selected Publications
Hongxing Lei and Paul E. Smith, The role
of the unfolded state in hairpin stability. Biophysical J., in
press, 2003.
Hongxing Lei and Paul E. Smith, Structure and dynamics
of chymotrypsin inhibitor 2 by computer simulation. J. Phys. Chem.
B, 107:1396-1402, 2003.
Samantha Weerasinghe and Paul E. Smith, A Kirkwood-Buff
derived force field for mixtures of urea and water. J. Phys. Chem.
B, 107:3891-3898, 2003.
Rajappa Chitra and Paul E. Smith, Molecular associations
in solution: A Kirkwood-Buff analysis of sodium chloride, ammonium
sulfate, guanidinium chloride, urea and 2,2,2-trifluoroethanol
in water. J. Phys. Chem. B, 106:1491-1500, 2002.
Mahalaxmi Aburi and Paul E. Smith, A conformational analysis
of leucine enkephalin as a function of pH. Biopolymers, 64:177-188,
2002.
Christopher A. Bottoms, Paul E. Smith and John J. Tanner,
A structurally conserved water molecule in Rossmann dinucleotide-binding
domains. Protein Sci., 11:2125-2137, 2002.
Publications continued... |
