Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution.

GUARDIA, CARLOS M.; ZEIDA, ARI; TRUJILLO, MADIA; RAFAEL RADI; MARIANO C. GONZÁLEZ LEBRERO; DARÍO A. ESTRIN

San Miguel de Tucuman

Congreso; XLI Reunión anual de la Sociedad Argentina de Biofísica.; 2012

Sociedad Argentina de Biofísica

The oxidation of cellular thiol-containing compounds is considered to play an important role in many biological processes such as redox signaling, detoxification of reactive oxygen and nitrogen species (ROS/RNS) and protein folding. Among possible oxidants, hydrogen peroxide H2O2 is known to be produced in many cell types as a response to a variety of extracellular stimuli and could work as an intracellular messenger. Despite its importance, the reaction is not completely understood at the atomic level. In this work, we elucidate the mechanism of thiol oxidation to disulfide by H2O2 (Scheme) for a model methanethiolate (CH3S-) system using state of the art hybrid quantum-classical (QM-MM) molecular dynamics simulations. Our results show that the solvent plays a key role in positioning the reactants in both reaction steps, that there is significant charge redistribution in the first stages of the reaction, and that there are several hydrogen transfer processes during the complete reaction pathway. Step 1: CH3S- + H2O2 → CH3SOH + HO- Step 2: CH3SOH + CH3S-/CH3SH → CH3SSH3C + HO-/H2O Scheme: Proposed mechanism of thiol oxidation by H2O2. Specifically, our results indicate that the first step is driven by a tendency of the slightly charged peroxidatic oxygen to become even more negative in the product via an electrophilic attack on the negative sulfur atom. This is inconsistent with the typical SN2 mechanism, which predicts a protonated sulfenic acid (CH3SOH) and hydroxyl anion (OH-) as stable intermediates. These intermediates are not found. Instead, the reaction proceeds directly to unprotonated sulfenic acid and water. However, the second step is a typical nucleophilic substitution of the hydroxyl group of sulfenic acid by the attacking methanethiolate(thiol). Surprisingly, when the final stage of the reaction is studied with the protonated nucleophile (CH3SH), the role of water is critical to enable the correct formation of more stable products: dimethyl disulfide (CH3SSH3C) and water.