The stable functional conformation of a protein depends entirely on the primary sequence of amino acids. This native structure is stable within a limited span of temperatures, pressures, and solvent conditions, and in globular proteins is stabilized by the formation of a hydrophobic core from which water is largely excluded. Few of the existing theoretical and computational investigations of protein stability treat water explicitly or are concerned with cold- or pressure-induced unfolding of proteins. We present simulations of a water-explicit heteropolymer protein model that exhibits heat-, cold-, and pressure-induced unfolding. We have previously developed a lattice model of a hydrophobic homopolymer in a hydrogen-bonding solvent. The model solvent, while simplified when compared to real water, displays many of water's thermodynamic anomalies, including a temperature of maximum density [1]. We have recently extended the model by incorporating both hydrophobic and polar monomers in the protein alphabet. Density of States simulations [2] of this model reproduce key features of experimentally-determined protein stability curves in the pressure-temperature plane. We explore the dependence of protein stability on the heteropolymer sequence, and identify specific patterns associated with thermal and mechanical stability. We also examine the effect of point mutations on the stability of individual sequences.

[1] S. Sastry, P.G. Debenedetti, F. Sciortino, and H.E. Stanley. Phys. Rev. E, 53: 6144-6154, 1996 [2] F.G. Wang and D.P. Landau. Phys. Rev. E, 64: 056101, 2001.

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