Backbone conformational dependence of peptide acidity

Electrostatic interactions at the protein surface yield over a billion-fold range of amide hydrogen exchange rates. This range is equivalent to the maximal degree of attenuation in exchange rates that have been shown to occur for amides buried within the protein interior. Continuum dielectric analysis of Ala-Ala, Ala-Gly, Gly-Ala and trans-Pro-Ala peptide conformer acidities predicts that the relative orientation of the two neighboring peptide groups can account for a million-fold variation in hydroxide-catalyzed hydrogen exchange rates. As in previous protein studies, an internal dielectric value of 3 was found to be applicable to simple model peptides, presumably reflecting the short lifetime of the peptide anion intermediate. Despite the million-fold range in conformer acidities, the small differences in the experimental exchange rates for these peptides are accurately predicted. Ala-Ala conformers with an extended N-terminal residue and the C-terminal residue in the α conformation are predicted to account for over 60% of the overall hydrogen exchange reaction, despite constituting only 12% of the protein coil population.