A Kirkwood-Buff Approach to Improved Cosolvent Force Fields

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Smith, Paul E.MCB-0090483Cosolvents can have dramatic effects on the properties of peptides and proteins in solution. They are often used to enhance the stability of proteins or to denature them in order to study protein folding. Exactly how cosolvents affect peptides and proteins is unknown. An understanding of these effects will greatly improve our current ideas concerning the nature of the denatured state of proteins. In turn, this will help to clarify the protein folding process by providing a well defined initial state from which one can rationalize the effects of temperature or denaturants. Experimental studies of the denatured states of proteins are limited due to the many conformations available to the protein, and an inability of techniques to determine the interactions between proteins and cosolvent molecules with atomic level resolution. In principle, computer simulations can provide atomic level resolution of denatured proteins and their interactions with cosolvents. However, computer simulation experimentsare only as reliable as the force fields which describe the interactions between the different species. In this proposal, it is shown that current cosolvent force fields need to be improvedin order to quantitatively reproduce the experimental properties of cosolvent mixtures with water. A combination of molecular dynamics simulation and the Kirkwood-Buff theory of mixtures will be used to provide sufficient data for comparison with experiment, and to ensure the quality of the force field. Both effective pair potentials and polarizable models will be investigated for sodium chloride, guanidinium chloride, urea, and 2,2,2 trifluoroethanol; which represent common cosolvents displaying a range of effects on peptides and proteins. The improved force fields will then be used to fully characterize, with atomic detail, the properties of these solutions. This is the first step in determining their different effects on proteins, and is absolutely essential if one is to have any confidence in computer simulation results for these systems.