Water and cold denaturation of small globular proteins

Cold denaturation is an intriguing phenomenon that deserves special attention because its rationalization is surely linked to a deeper understanding of the molecular determinants of the marginal stability of small globular proteins dissolved in water and aqueous solutions. It is here reviewed and discussed a theoretical approach that has offered a reliable explanation for the occurrence of both cold and hot denaturations. A cornerstone of the approach is the recognition of the role played by the density of water and its temperature-dependence that are largely determined by the special energetic and geometric features of H-bonds. In fact, the density of water determines the magnitude of the solvent-excluded volume effect, which is a main ingredient of the hydrophobic effect. The relationship between density and solvent-excluded volume effect establishes a strong connection between the physico-chemical properties of water and the conformational stability of small globular proteins.