We study the stability of globular proteins as a function of temperature and pressure through $NPT$ simulations of a coarse-grained model. We reproduce the elliptical stability of proteins and highlight a unifying microscopic mechanism for pressure and cold denaturations. The mechanism involves the solvation of nonpolar residues with a thin layer of water. These solvated states have lower volume and lower hydrogen-bond energy compared to other conformations of nonpolar solutes. Hence, these solvated states are favorable at high pressure and low temperature, and they facilitate protein unfolding under these thermodynamical conditions.

• Received 11 March 2012

DOI:https://doi.org/10.1103/PhysRevLett.109.048104