Protein Interactions and Solvation in Binary Solvents

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We propose to continue our studies of the effect of solvation on the conformational preferences and interactions of proteins. During the requested budget period, we propose to carry out volumetric and spectroscopic experiments as well as molecular dynamics (MD) simulations which are designed to achieve the following specific aims: comparative and syste¬matic investigation of solvation of the 20 naturally existing amino acid side chains in N-acetyl amino acid amides in water and binary mixtures of water and water-soluble denaturing and stabilizing cosolvents; thermodynamic characterization of the association of various cosolvents with individual protein groups; volumetric characterization of solvation of native and unfolded proteins in denaturing and stabilizing cosolvents and exploration of the ad¬ditivity of protein sol¬vation; and comparative characterization of protein folding and binding reactions in water and denaturing and stabilizing cosolvents. The domineering influence of solvent on chemical equi¬libria involving proteins is unanimously acknowledged. In fact, any protein reaction in an aqu¬eous solution can be considered as replacement of solute-solvent with solute-solute interac¬tions. With this notion, it is clear that the thermodynamics of solute-solvent and solute-cosolvent interactions is an important integral part of the reaction thermodynamics. Our proposed volu¬met¬ric studies on low molecular weight model compounds amplified by the statistical thermo¬dynamic interpretation algorithm and MD simulations will enable us to quantify the differential affinity of protein functional groups for water and stabilizing and denaturing osmolytes. Exten¬ding these studies to proteins will permit us to investigate nonadditive solvation effects in the folded and unfolded conformations. Finally, characterization of protein folding and binding reactions in binary solvents will test our basic conclusions on real biological systems.