One-Electron Oxidation of Methionine in Peptide Environments: The Effect of Three-Electron Bonding on the Reduction Potential of the Radical Cation

Abstract

The complexes between the radical cation of dimethyl sulfide 2 and models for eight biologically available electron pair donors, :X (:X = H2O (2a), H2CO (2b), HC(O)NH2 (2c), HC(O)NHCH3 (2d), HCO2- (2e), HCO3- (2f), H2PO4- (2g), and CH3NH2 (2h)), were optimized at the B3LYP/6-31G(d) level of theory. S∴X bond dissociation enthalpies (BDEs) were determined by single point calculations at the CBS−RAD level, a method designed for quantitative thermochemistry of free radicals. The effect of solvation was determined by application of a polarizable continuum model. Only the amine complex is predicted to be stable in water. H2O and H2PO4- make transient complexes, and the remaining complexes are predicted to dissociate spontaneously. The dissociation is driven by entropy and conformationally constrained complexes are predicted to be stable in water. Reduction potentials, E°, accurate to ±0.1 V were calculated for the complexes with dimethyl sulfide and for the amino acid, methionine, both as an isolated amino acid and incorporated into a polypeptide at the N- and C-terminals and midchain. Stabilization of the radical cation of Met by three-electron bonding is predicted if an S∴N bond can be formed to a free amino group, as in N-terminal Met or a nearby Lys. Likewise, Met oxidation is facilitated by phosphodiesters, but not by carboxylate groups or amide groups. No lowering of E° is predicted for C-terminal Met or for midchain Met. The implications of the results for the redox chemistry associated with Alzheimer's disease are discussed.