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

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 <i>N</i>-formylmethioninamide (<b>11</b>^•<b><i>⁺</i></b>) and two model systems, dimethyl sulfide (<b>1</b>^•<b><i>⁺</i></b>) and ethyl methyl sulfide (<b>6</b>^•<b><i>⁺</i></b>), in the presence of oxygen have been studied by B3LYP/6-31G(d) and CBS-RAD calculations. The stable form of <b>11</b>^•<b><i>⁺</i></b> has a three-electron bond between the sulfur radical cation and the carbonyl oxygen atom of the <i>i </i><i>−</i> 1 residue. The radical cation may lose a proton from the methyl or methylene groups flanking the oxidized sulfur. Both <b>11</b>^•<b><i>⁺</i></b> 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 <b>1</b>^•<b><i>⁺</i></b> + 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 (Δ<i>G</i> = 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.