Water-mediated interactions destabilize proteins.

Proteins are folded to avoid exposure of the nonpolar groups to water because water-mediated interactions between nonpolar groups are a promising factor in the thermodynamic stabilities of proteins-which is a well-accepted view as one of the unique effects of hydrophobic interactions. This article poses a critical question for this classical view by conducting an accurate solvation free-energy calculation for a thermodynamic cycle of a protein folding using a liquid-state density functional theory. Here, the solvation-free energy for a leucine zipper formation was examined in the coiled-coil protein GCN4-p1, a typical model for hydrophobic interactions, which demonstrated that water-mediated interactions were unfavorable for the association of nonpolar groups in the native state, while the dispersion forces between them were, instead, responsible for the association. Furthermore, the present analysis well predicted the isolated helical state stabilized by pressure, which was previously observed in an experiment. We reviewed the problems in the classical concept and semiempirical presumption that the energetic cost of the hydration of nonpolar groups is a driving force of folding.