Local water bridges and protein conformational stability

Recent studies have pointed out the important role of local water structure s in protein conformational stability. Here, we present an accurate and com putationally effective way to estimate the free energy contribution of the simplest water structure motif-the water bridge. Based on the combination o f empirical parameters for accessible protein surface area and the explicit consideration of all possible water bridges with the protein, we introduce an improved protein solvation model. We find that accounting for water bri dge formation in our model is essential to understand the conformational be havior of polypeptides in water. The model formulation, in fact, does not d epend on the polypeptide nature of the solute and is therefore applicable t o other flexible biomolecules (i.e., DNAs, RNAs, polysaccharides, etc.).