Conformational Flexibility Controls Proton Transfer between the Methionine Hydroxy Sulfuranyl Radical and the N-Terminal Amino Group in Thr−(X)n−Met Peptides

For Thr−(X)n−Met peptides, we have correlated the efficiency of proton transfer and an intramolecular radical reaction between a methionyl hydroxy sulfuranyl radical and the N-terminus with the flexibility of the spacer sequence −(X)n−, X = Gly and Pro and n = 0−4. Hydroxy sulfuranyl radicals accept a proton from the N-terminus to yield a cyclic (S∴Ν)+ three-electron-bonded intermediate which ultimately expels acetaldehyde. Acetaldehyde formation was used to quantify the efficiency of proton transfer and cyclization, whereas peptide flexibility was calculated by molecular modeling methods. For X = Gly, proton transfer and cyclization proceeds in a concerted manner, and peptide flexibility mainly controls the proton transfer step. For X = Pro, no low-energy conformation was located, which allows concerted proton transfer and cyclization, indicating that proton transfer occurs over longer distances, likely via bridging water molecules. These sequence-dependent differences are reflected in different β-values for the proton-transfer step, β = 0.66 ± 0.02 Å-1 for X = Gly and β ≈ 0.12 ± 0.1 Å-1 for X = Pro.