Solution environmental conditions such as temperature and pressure strongly influence whether a protein favors the compact, native or the unfolded, denatured state. Protein collapse from the unfolded state is mainly driven by the formation of a hydrophobic core, due to favorable hydrophobic-hydrophobic amino acid residue interactions. Therefore, factors that affect this interaction strength influence whether a protein can maintain its native state. The thermal stability of a protein chain has been previously explored as a balance between hydrophobic interactions and chain configurational entropy at ambient pressure through a heteropolymer collapse theory developed by Dill and coworkers [1].

In this talk, we extend this theory to also account for pressure effects on the hydration of hydrophobic residues. In particular, we estimate the strength of the hydrophobic interactions using a molecular thermodynamic model for the interfacial free energy between liquid water and a curved hydrophobic solute. The model, which also reproduces many of the distinctive thermodynamic properties of aqueous solutions in bulk and interfacial environments, predicts that the water-solute interfacial free energy is significantly reduced by the application of high hydrostatic pressures. This allows water to penetrate into folded heteropolymers at high pressure and break apart their hydrophobic cores, a scenario suggested earlier by information theory calculations [2]. As a result, folded heteropolymers are predicted to display the kind of closed region of stability in the pressure-temperature plane exhibited by native proteins. We compare predictions of the collapse theory with experimental data for several proteins.

[1] K. A. Dill, D. O. V. Alonso, and K. Hutchinson. Biochemistry, 28: 5439-5449, 2006.

[2] G. Hummer, S. Garde, A. E. Garcia, A. Pohorille, and L. R. Pratt. Proc. Natl. Acad. Sci., 93 :8951-8955, 1996.