Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm
The oxidation of cellular thiol-containing compounds, such as glutathione and protein Cys residues, is considered to play an important role in many biological processes. Among possible oxidants, hydrogen peroxide (H 2O 2) is known to be produced in many cell types as a response to a variety of extra...
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todo:paper_0893228X_v25_n3_p741_Zeida2023-10-03T15:41:43Z Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm Zeida, A. Babbush, R. González Lebrero, M.C. Trujillo, M. Radi, R. Estrin, D.A. hydrogen peroxide hydroxyl group methanethiol oxygen sulfenic acid derivative sulfur thiol transition element water aqueous solution article chemical reaction electrophilicity molecular dynamics oxidation Hydrogen Peroxide Molecular Dynamics Simulation Oxidation-Reduction Sulfhydryl Compounds The oxidation of cellular thiol-containing compounds, such as glutathione and protein Cys residues, is considered to play an important role in many biological processes. Among possible oxidants, hydrogen peroxide (H 2O 2) 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. This reaction has been reported to proceed through a S N2 mechanism, but despite its importance, the reaction is not completely understood at the atomic level. In this work, we elucidate the reaction mechanism of thiol oxidation by H 2O 2 for a model methanethiolate 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, that there is a significant charge redistribution in the first stages of the reaction, and that there is a hydrogen transfer process between H 2O 2 oxygen atoms that occurs after reaching the transition state. These observations challenge the S N2 mechanism hypothesis for this reaction. Specifically, our results indicate that the reaction 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 S N2 mechanism, which predicts a protonated sulfenic acid and hydroxyl anion as stable intermediates. These intermediates are not found. Instead, the reaction proceeds directly to unprotonated sulfenic acid and water. © 2012 American Chemical Society. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_0893228X_v25_n3_p741_Zeida |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
hydrogen peroxide hydroxyl group methanethiol oxygen sulfenic acid derivative sulfur thiol transition element water aqueous solution article chemical reaction electrophilicity molecular dynamics oxidation Hydrogen Peroxide Molecular Dynamics Simulation Oxidation-Reduction Sulfhydryl Compounds |
| spellingShingle |
hydrogen peroxide hydroxyl group methanethiol oxygen sulfenic acid derivative sulfur thiol transition element water aqueous solution article chemical reaction electrophilicity molecular dynamics oxidation Hydrogen Peroxide Molecular Dynamics Simulation Oxidation-Reduction Sulfhydryl Compounds Zeida, A. Babbush, R. González Lebrero, M.C. Trujillo, M. Radi, R. Estrin, D.A. Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm |
| topic_facet |
hydrogen peroxide hydroxyl group methanethiol oxygen sulfenic acid derivative sulfur thiol transition element water aqueous solution article chemical reaction electrophilicity molecular dynamics oxidation Hydrogen Peroxide Molecular Dynamics Simulation Oxidation-Reduction Sulfhydryl Compounds |
| description |
The oxidation of cellular thiol-containing compounds, such as glutathione and protein Cys residues, is considered to play an important role in many biological processes. Among possible oxidants, hydrogen peroxide (H 2O 2) 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. This reaction has been reported to proceed through a S N2 mechanism, but despite its importance, the reaction is not completely understood at the atomic level. In this work, we elucidate the reaction mechanism of thiol oxidation by H 2O 2 for a model methanethiolate 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, that there is a significant charge redistribution in the first stages of the reaction, and that there is a hydrogen transfer process between H 2O 2 oxygen atoms that occurs after reaching the transition state. These observations challenge the S N2 mechanism hypothesis for this reaction. Specifically, our results indicate that the reaction 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 S N2 mechanism, which predicts a protonated sulfenic acid and hydroxyl anion as stable intermediates. These intermediates are not found. Instead, the reaction proceeds directly to unprotonated sulfenic acid and water. © 2012 American Chemical Society. |
| format |
JOUR |
| author |
Zeida, A. Babbush, R. González Lebrero, M.C. Trujillo, M. Radi, R. Estrin, D.A. |
| author_facet |
Zeida, A. Babbush, R. González Lebrero, M.C. Trujillo, M. Radi, R. Estrin, D.A. |
| author_sort |
Zeida, A. |
| title |
Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm |
| title_short |
Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm |
| title_full |
Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm |
| title_fullStr |
Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm |
| title_full_unstemmed |
Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm |
| title_sort |
molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: challenging the s n2 paradigm |
| url |
http://hdl.handle.net/20.500.12110/paper_0893228X_v25_n3_p741_Zeida |
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