Implicit modeling of nonpolar solvation for simulating protein folding and conformational transitions

Abstract

Accurate description of the solvent environment is critical in computer simulations of protein structure and dynamics. An implicit treatment of solvent aims to capture the mean influence of water molecules on the solute via direct estimation of the solvation free energy. It has emerged as a powerful alternative to explicit solvent, and provides a favorable compromise between computational cost and level of detail. We review the current theory and techniques for implicit modeling of nonpolar solvation in the context of simulating protein folding and conformational transitions, and discuss the main directions for further development. It is demonstrated that the current surface area based nonpolar models have severe limitations, including insufficient description of the conformational dependence of solvation, over-estimation of the strength of pair-wise nonpolar interactions, and incorrect prediction of anti-cooperativity for three-body hydrophobic associations. We argue that, to improve beyond current level of accuracy of implicit solvent models, two important aspects of nonpolar solvation need to be incorporated, namely, the length-scale dependence of hydrophobic association and solvent screening of solute–solute dispersion interactions. We recognize that substantial challenges exist in constructing a sufficiently balanced, yet reasonably efficient, implicit solvent protein force field. Nonetheless, most of the fundamental problems are understood, and exciting progress has been made over the last few years. We believe that continual work along the frontiers outlined will greatly improve one’s ability to study protein folding and large conformational transitions at atomistic detail.