Heteropolymer collapse theory for protein folding in the pressure-temperature plane.

We revisit a heteropolymer collapse theory originally introduced to explore how the balance between hydrophobic interactions and configurational entropy determines the thermal stability of globular proteins at ambient pressure. We generalize the theory by introducing a basic statistical mechanical treatment for how pressure impacts the solvent-mediated interactions between hydrophobic amino-acid 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. 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.