Protein crystallization is typically induced by the addition of precipitating agents: inorganic salts (e.g., NH4SO4, NaCl), organic co-solvents (e.g., ethanol, ethylene glycol) or polymers (e.g., PEG). However, the underlying molecular mechanisms that govern how these precipitating agents induce protein precipitation are still unclear. It is widely believed that the precipitating agents preferentially partition into bulk aqueous solution, rather than near the protein surface, which in turn, leads to protein phase separation. The partitioning of solvent (water) and co-solvents (precipitating agents) near the protein surface relative to bulk solution is quantified by the preferential interaction parameter. Kirkwood Buff (KB) theory provides a rigorous statistical thermodynamic framework for calculating the preferential interaction parameter in terms of radial distribution functions extracted from molecular dynamics (MD) simulations. However, a limitation in the application of KB theory is the convergence of the KB integrals containing these radial distribution functions. The approach we have taken to overcome this limitation is an extension of the approach proposed by Lockwood and Rossky to evaluate the partial molar volumes and compressibilities of methanol and ethanol in water. Taking advantage of the fact that KB integral does not depend on any specific site in defining the radial distribution function, the oscillations in radial distribution function can be damped by smearing out the solvent/co-solvent molecular structures over a distribution of auxiliary sites within a pre-determined screening radius. We apply this approach to investigate preferential interactions and its influence on the potential of mean force between solute molecules at different co-solvent concentrations. Results will be presented for the preferential partitioning of water and alcohol co-solvents near the surface of well-characterized molecular solutes, as well as small globular proteins.

Reference:

1. Lockwood, D. M.; Rossky, P. J. Evaluation of functional group contributions to excess volumetric properties of solvated molecules. J. Phys. Chem. B. 1999, 103, 1982.