Sidechain conformational dependence of hydrogen exchange in model peptides
Abstract
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...Continue Reading
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Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins
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