Molecular Basis of the Mechanism of Thiol Oxidation by Hydrogen Peroxide in Aqueous Solution: Challenging the SN2 Paradigm

ZEIDA, A.; BABBUSH, R.; M. C. GONZALEZ LEBRERO; TRUJILLO, M.; RADI, R.; ESTRIN, D.A.

CHEMICAL RESEARCH IN TOXICOLOGY (WASHINGTON)

AMER CHEMICAL SOC

Lugar: Washington; Año: 2012 vol. 25 p. 741 - 746

0893-228X

ABSTRACT: The oxidation of cellular thiol-containingcompounds, such as glutathione and protein Cys residues, isconsidered to play an important role in many biologicalprocesses. Among possible oxidants, hydrogen peroxide (H2O2)is known to be produced in many cell types as a response to avariety of extracellular stimuli and could work as an intracellularmessenger. This reaction has been reported to proceed througha SN2 mechanism, but despite its importance, the reaction is notcompletely understood at the atomic level. In this work, weelucidate the reaction mechanism of thiol oxidation by H2O2 fora model methanethiolate system using state of the art hybrid quantum-classical (QM-MM) molecular dynamics simulations. Ourresults show that the solvent plays a key role in positioning the reactants, that there is a significant charge redistribution in thefirst stages of the reaction, and that there is a hydrogen transfer process between H2O2 oxygen atoms that occurs after reachingthe transition state. These observations challenge the SN2 mechanism hypothesis for this reaction. Specifically, our resultsindicate that the reaction is driven by a tendency of the slightly charged peroxidatic oxygen to become even more negative in theproduct via an electrophilic attack on the negative sulfur atom. This is inconsistent with the SN2 mechanism, which predicts aprotonated sulfenic acid and hydroxyl anion as stable intermediates. These intermediates are not found. Instead, the reactionproceeds directly to unprotonated sulfenic acid and water.