Solvation and desolvation effects in protein folding: native flexibility, kinetic cooperativity and enthalpic barriers under isostability conditions.

As different parts of a protein chain approach one another during folding, they are expected to encounter desolvation barriers before optimal packing is achieved. This impediment originates from the water molecule's finite size, which entails a net energetic cost for water exclusion when the formation of compensating close intraprotein contacts is not yet complete. Based on recent advances, we extend our exploration of these microscopic elementary desolvation barriers' roles in the emergence of generic properties of protein folding. Using continuum Gō-like C(alpha) chain models of chymotrypsin inhibitor 2 (CI2) and barnase as examples, we underscore that elementary desolvation barriers between a protein's constituent groups can significantly reduce native conformational fluctuations relative to model predictions that neglected these barriers. An increasing height of elementary desolvation barriers leads to thermodynamically more cooperative folding/unfolding transitions (i.e., higher overall empirical folding barriers) and higher degrees of kinetic cooperativity as manifested by more linear rate-stability relationships under constant temperature. Applying a spatially non-uniform thermodynamic parametrization we recently introduced for the pairwise C(alpha) potentials of mean force, the present barnase model further illustrates that desolvation is a probable physical underpinning for the experimentally observed high intrinsic enthalpic folding barrier under isostability conditions.