Hydrophobic Effect: The Entropic Structure of the Protein Hydration Interface

Abstract

Characterizing the interactions between protein and water is quintessential to protein folding and dynamics. As the driving force of protein folding, the hydrophobic effect is mainly characterized by burial of non-polar surface area that indirectly measures the increase in water entropy. A more direct approach is to understand how polar and nonpolar residues arrange on the protein surface in a way to maximize the entropy of solvating water, which minimizes the chemical potential of overall folded protein system. At the protein-water interface, distribution of hydrophilic and hydrophobic groups determines the arrangement of water molecules, which directly relates to the water entropy. In maximizing water entropy, proteins need to minimally disturb water's hydrogen bonding network by presenting interfaces very close to water: the polar group distribution on the protein surface should mimic the bulk water structure. To investigate water entropy, many near native protein structures in water were simulated using molecular dynamics. A dynameomics library of over 400 protein domains were run using the CHARMM force field implemented in the NAMD package. The distribution of pairwise polar atom distances connected through the hydrogen bonding network of waters were collected and analyzed. The polar group distribution holds a striking resemblance to the radial distribution function of bulk water. The distribution of polar groups are also classified depending upon the secondary structure, and are also categorized according to the nature of the polar group atoms such as side chain atoms and backbone atoms. Because these results imply that the entropy of water can be directly calculated from the distribution of polar groups on the protein surface, this research provides a stepping-stone in developing more accurate potential functions to describe solvation free energies of proteins.