Desolvation Penalty for Burying Hydrogen-Bonded Peptide Groups in Protein Folding

A novel analysis of the enthalpy of protein unfolding is proposed and used to test for a desolvation penalty when hydrogen-bonded peptide groups are desolvated via folding. The unfolding enthalpy has three components, (I) the change when peptide hydrogen bonds are broken and the exposed -CO and -NH groups are solvated, (2) the change when protein-protein van der Waals interactions are broken and replaced by protein-water van der Waals interactions, and (3) the change produced by the hydrophobic interaction when nonpolar groups in the protein interior (represented as a liquid hydrocarbon) are transferred to water. A key feature of the analysis is that the enthalpy change from the hydrophobic interaction goes through 0 at 22 degrees C according to the liquid hydrocarbon model. Protein unfolding enthalpies are smaller at 22 degrees C than the enthalpy change for unfolding an alanine peptide helix. Data in the literature indicate that the van der Waals contribution to the unfolding enthalpy is considerably larger than the unfolding enthalpy itself at 22 degrees C, and therefore, a sizable desolvation penalty is predicted. Such a desolvation penalty was predicted earlier from electrostatic calculations of a stabilizing interaction between water and the hydrogen-bonded peptide group.