Reactions of One-Electron-Oxidized Methionine with Oxygen: An ab Initio Study

Abstract

A one-electron oxidation of a methionine residue is thought to be a key step in the neurotoxicity of the beta amyloid peptide of Alzheimer's disease. The chemistry of the radical cation of N-formylmethioninamide (11•+) and two model systems, dimethyl sulfide (1•+) and ethyl methyl sulfide (6•+), in the presence of oxygen have been studied by B3LYP/6-31G(d) and CBS-RAD calculations. The stable form of 11•+ has a three-electron bond between the sulfur radical cation and the carbonyl oxygen atom of the i − 1 residue. The radical cation may lose a proton from the methyl or methylene groups flanking the oxidized sulfur. Both 11•+ and the resultant C-centered radicals may add oxygen to form peroxy radicals. The calculations indicate that unlike C-centered radicals the sulfur radical cation does not form a covalent bond to oxygen but rather forms a loose ion-induced dipole complex with an S−O separation of about 2.7 Å, and is bound by about 13 kJ mol-1 (on the basis of 1•+ + O2). Direct intramolecular abstraction of an H atom from the αC site is unlikely. It is endothermic by more than 20 kJ mol-1 and involves a high barrier (ΔG = 79 kJ mol-1). The α-to-S C-centered radicals will add oxygen to form peroxy radicals. The OH BDEs of the parent hydroperoxides are in the range of 352−355 kJ mol-1, similar to SH BDEs (360 kJ mol-1) and αC−H BDEs (345−350 kJ mol-1). Thus, the peroxy radicals are oxidizing species comparable in strength to thiyl radicals and peptide backbone αC-centered radicals. Each peroxy radical can abstract a hydrogen atom from the backbone αC site of the Met residue to yield the corresponding αC-centered radical/hydroperoxide in a weakly exothermic process with modest barriers in the range of 64−92 kJ mol-1.