(231a) Protein-Solvent Attractive Interactions Dominate the Inverse Temperature of Polypeptide Hydration Free Energies

Simulations show that both the excess free energy and the excess enthalpy of hydration of a deca-alanine peptide in the helix and extended (coil) states increases with increasing temperature: as expected of a hydrophobic solute, the excess entropy of hydration is negative and the excess heat capacity of hydration is positive. A similar trend is also found for a helix-pair, a simple model for a protein tertiary structure: as expected in protein unfolding, we find a positive heat capacity change in the unpairing of a helix dimer. However, the temperature dependency of the excess enthalpy is dominated by different physics for methane, the side-chain analog of alanine and a prototypical hydrophobe, and the polypeptides. For methane, the temperature signatures arise due to changes in water reorganization, but for the peptide models, it is due to weakening of the effective attractive solute-solvent interactions, a major fraction of which arises from peptide backbone-solvent interactions. Different temperature dependencies are also observed for the excess free energy of a cavity, an ideal hydrophobe: increasing with temperature for methane, but decreasing for the proteins.

These first, direct, all-atom calculations of the thermodynamics of hydration of protein models shows that acknowledging the role of attractive interactions and the expansion of the solvent matrix upon heating provides a parsimonious explanation for the unusual temperature signatures that have often been explained by invoking hydrophobic hydration. Implications of this work for understanding cold denaturation and for understanding intrinsic disorder and aggregation will be noted.