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                                             BIOINFORMATICS COLLOQUIUM
						College of Science
                                              George Mason University
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Folding in the Cell: Predicting the effect of osmolytes on the thermodynamics and folding kinetics of globular proteins
						 
                                                 Edward O'Brien
					     University of Maryland


Abstract:
Osmolytes, a class of small molecules that occur naturally in the human body, 
can have signicant effects on the equilibrium properties of proteins. Therefore, 
accurate prediction of the impact osmolytes have on the dynamics and thermodynamic 
properties of proteins is of profound biophysical interest. Recently it has recently 
shown that it is possible to accurately predict osmolyte induced changes in the 
folding/unfolding free energy of a protein using experimental data on transfer free 
energies of amino-acid sidechains and the peptide backbone. We have developed a theory
called Chemical Perturbation Theory (CPT) that predicts osmolyte induced changes 
in any thermodynamic property, not just changes in folding free energies.
CPT is a statistical-mechanical theory that combines information from experimental 
transfer free energies of sidechains and the peptide backbone with computer simulations 
and a free energy perturbation method. While CPT gives detailed information on 
thermodynamic properties, it contains no information on protein dynamics. To study 
protein dynamics in an aqueous osmolyte solution we develop an implicit solvent 
model we call the `Tanford Implicit Solvent Model' (TISM), that is based on the 
Tanford transfer model. Using this implicit solvent model we study the impact of 
urea and trimethylamine-N-oxide (TMAO) on protein folding pathways and kinetics of 
globular proteins with all alpha, and mixed alpha/beta topologies. With these two 
tools (CPT and TISM) we are able to model folding reactions that can occur in the 
cellular millieu.