Sidechain conformational dependence of hydrogen exchange in model peptides

Peptide hydrogens that are exposed to solvent in protein X-ray structures exhibit a billion-fold range in hydroxide-catalyzed exchange rates, and these rates have previously been shown to be predictable by continuum dielectric methods to within a factor of 7, based on single protein conformations. When using a protein coil library to model the Boltzmann-weighted conformational distribution for the various N-acetyl-[X-Ala]-N-methylamides and N-acetyl-[Ala-Y]-N-methylamides, the acidity of the central amide in the individual conformers of each peptide spans nearly a million-fold range. Nevertheless, population averaging of these conformer acidities predicts the standard sidechain-dependent hydrogen exchange correction factors for nonpolar model peptides to within a factor of 30% (10(0.11)) with a correlation coefficient r=0.91. Comparison with the analogous continuum dielectric calculations for the other N-acetyl-[X-Y]-N-methylamides indicates that deviations from the isolated residue hypothesis of classical polymer theory predict appreciable errors in the exchange rates for conformationally disordered peptides when the standard sidechain-dependent hydrogen exchange rate correction factors are assumed to be independently additive. Although electronic polarizability generally dominates the dielectric shielding for the approximately 10ps lifetime of peptide ionization, evidence is presented for modest contributions from rapid intrarotamer conformational reorganization of Asn and Gln sidechains.