Origin of the change in solvation enthalpy of the peptide group when neighboring peptide groups are added

Abstract

Recent calorimetric measurements of the solvation enthalpies of some dipeptide analogs confirm our earlier prediction that the principle of group additivity is not valid for the interaction of the peptide group with water. We examine the consequences for understanding the properties of peptide solvation. A major consequence is that the current value of the peptide-solvation enthalpy, which is a basic parameter in analyzing the energetics of protein folding, is seriously wrong. Electrostatic calculations of solvation-free energies provide an estimate of the size and nature of the error. Peptide hydrogen exchange rates provide an experimental approach for testing the accuracy of the solvation-free energies of peptide groups found by electrostatic calculations. These calculations emphasize that ignoring electrostatic interactions with neighboring NHCO groups should be a major source of error. Results in 1972 for peptide hydrogen exchange rates demonstrate that peptide-solvation-free energies are strongly affected by adjoining NHCO groups. In the past, the effect of adjoining peptide groups on the exchange rate of a peptide NH proton was treated as an inductive effect. The effect can be calculated, however, by an electrostatic model with fixed partial charges and a continuum solvent.