Recent studies have pointed out the important role
of local water structures in protein conformational stability.
Here, we present an accurate and computationally effective
way to estimate the free energy contribution of the simplest
water structure motif—the water bridge. Based on
the combination of 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 bridge formation in our model is essential to
understand the conformational behavior of polypeptides
in water. The model formulation, in fact, does not depend
on the polypeptide nature of the solute and is therefore
applicable to other flexible biomolecules (i.e., DNAs,
RNAs, polysaccharides, etc.).