Dialkyl sulphur radical cations: competition between proton and methyl cation transfers to sulphur nucleophiles: an ab initio study

Abstract

Ab initio calculations were performed on model compounds to examine the possibility of conversion of one-electron-oxidized methionine to homocysteine radical under physiologically relevant conditions. Specifically, we studied competitive proton and methyl cation transfer from the dimethyl sulphide radical cation to three neutral, closed-shell sulphur bases/nucleophiles: H₂S, CH₃SH and (CH₃)₂S. The latter two are models for cysteine (or homocysteine) and methionine, respectively. Calculations were performed at the B3LYP/6-31G(d) and

levels. The enthalpies of reaction and free energies were determined at 298 K in the gaseous phase and in aqueous solution. CPCM solvation calculations were employed for the solution phase to obtain free energies of solvation. For all three sulphur bases, proton transfer from oxidized (CH₃)₂S is endothermic and is not hindered by a barrier. Nucleophilic attack by (CH₃)₂S at the methyl group is strongly exothermic and is impeded by a low enthalpic barrier (

 kJ mol⁻¹). The entropy of activation serves to raise the barrier (

 kJ mol⁻¹) and unfavourable aqueous solvation of the transition structure raises it even further (

 kJ mol⁻¹). It is concluded on the basis of the model systems that demethylation of oxidized methionine to give homocysteine would not be observed in an aqueous environment, but may be observable under hydrophobic conditions that exist in the beta amyloid fibrils of Alzheimer's disease.

Acknowledgements

Financial support from the Natural Sciences and Engineering Council of Canada (NSERC) and the Alzheimer Society of Canada is gratefully acknowledged. The authors thank David A. Armstrong and Patrick Brunelle for useful discussions.