Molecular Basis of the Mechanism of Thiol Oxidation by Hydrogen Peroxide in Aqueous Solution: Challenging the SN2 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 (H2O2) is known to be produced in many cell types as a response to a variety of extrace...
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creator | Zeida, Ari Babbush, Ryan González Lebrero, Mariano C Trujillo, Madia Radi, Rafael Estrin, Darío A |
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 (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. This reaction has been reported to proceed through a SN2 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 H2O2 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 H2O2 oxygen atoms that occurs after reaching the transition state. These observations challenge the SN2 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 SN2 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. |
doi_str_mv | 10.1021/tx200540z |
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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. This reaction has been reported to proceed through a SN2 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 H2O2 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 H2O2 oxygen atoms that occurs after reaching the transition state. These observations challenge the SN2 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 SN2 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.</description><identifier>ISSN: 0893-228X</identifier><identifier>EISSN: 1520-5010</identifier><identifier>DOI: 10.1021/tx200540z</identifier><identifier>PMID: 22303921</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Hydrogen Peroxide - chemistry ; Molecular Dynamics Simulation ; Oxidation-Reduction ; Sulfhydryl Compounds - chemistry</subject><ispartof>Chemical research in toxicology, 2012-03, Vol.25 (3), p.741-746</ispartof><rights>Copyright © 2012 American Chemical Society</rights><rights>2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/tx200540z$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/tx200540z$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22303921$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zeida, Ari</creatorcontrib><creatorcontrib>Babbush, Ryan</creatorcontrib><creatorcontrib>González Lebrero, Mariano C</creatorcontrib><creatorcontrib>Trujillo, Madia</creatorcontrib><creatorcontrib>Radi, Rafael</creatorcontrib><creatorcontrib>Estrin, Darío A</creatorcontrib><title>Molecular Basis of the Mechanism of Thiol Oxidation by Hydrogen Peroxide in Aqueous Solution: Challenging the SN2 Paradigm</title><title>Chemical research in toxicology</title><addtitle>Chem. Res. Toxicol</addtitle><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 (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. This reaction has been reported to proceed through a SN2 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 H2O2 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 H2O2 oxygen atoms that occurs after reaching the transition state. These observations challenge the SN2 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 SN2 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.</description><subject>Hydrogen Peroxide - chemistry</subject><subject>Molecular Dynamics Simulation</subject><subject>Oxidation-Reduction</subject><subject>Sulfhydryl Compounds - chemistry</subject><issn>0893-228X</issn><issn>1520-5010</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1PwkAU3BiNIHrwD5i9eKy-3W1L68EEiYoJCAmYeNs82m27pOxiPwzw6y2iRE_v5c28SWaGkEsGNww4u63WHMBzYXtE2szj4HjA4Ji0IQiFw3nw3iJnZbkAYA29e0panAsQIWdtsh3ZXEV1jgV9wFKX1Ca0yhQdqShDo8vl7jDLtM3peK1jrLQ1dL6hg01c2FQZOlGFbQBFtaG9j1rZuqRTm9c74h3tZ5jnyqTapN-y01dOJ1hgrNPlOTlJMC_Vxc_skLenx1l_4AzHzy_93tBB7kPlMKF8EbDQTQLuKZ7EIYqAx9BNIIxZEKDrQhxxFxvjiet7whU-w9DzxTxizSI65H6vu6rnSxVHylQF5nJV6CUWG2lRy_-I0ZlM7acUAgK_CapDrv4KHD5_U2wI13sCRqVc2LowjR_JQO7akYd2xBfhSoBf</recordid><startdate>20120319</startdate><enddate>20120319</enddate><creator>Zeida, Ari</creator><creator>Babbush, Ryan</creator><creator>González Lebrero, Mariano C</creator><creator>Trujillo, Madia</creator><creator>Radi, Rafael</creator><creator>Estrin, Darío A</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>5PM</scope></search><sort><creationdate>20120319</creationdate><title>Molecular Basis of the Mechanism of Thiol Oxidation by Hydrogen Peroxide in Aqueous Solution: Challenging the SN2 Paradigm</title><author>Zeida, Ari ; Babbush, Ryan ; González Lebrero, Mariano C ; Trujillo, Madia ; Radi, Rafael ; Estrin, Darío A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a260t-13e638194f825e2fd9a382d07f09d188a440dc24a520f46534361a9563bc11a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Hydrogen Peroxide - chemistry</topic><topic>Molecular Dynamics Simulation</topic><topic>Oxidation-Reduction</topic><topic>Sulfhydryl Compounds - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zeida, Ari</creatorcontrib><creatorcontrib>Babbush, Ryan</creatorcontrib><creatorcontrib>González Lebrero, Mariano C</creatorcontrib><creatorcontrib>Trujillo, Madia</creatorcontrib><creatorcontrib>Radi, Rafael</creatorcontrib><creatorcontrib>Estrin, Darío A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemical research in toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zeida, Ari</au><au>Babbush, Ryan</au><au>González Lebrero, Mariano C</au><au>Trujillo, Madia</au><au>Radi, Rafael</au><au>Estrin, Darío A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular Basis of the Mechanism of Thiol Oxidation by Hydrogen Peroxide in Aqueous Solution: Challenging the SN2 Paradigm</atitle><jtitle>Chemical research in toxicology</jtitle><addtitle>Chem. Res. Toxicol</addtitle><date>2012-03-19</date><risdate>2012</risdate><volume>25</volume><issue>3</issue><spage>741</spage><epage>746</epage><pages>741-746</pages><issn>0893-228X</issn><eissn>1520-5010</eissn><abstract>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 (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. This reaction has been reported to proceed through a SN2 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 H2O2 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 H2O2 oxygen atoms that occurs after reaching the transition state. These observations challenge the SN2 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 SN2 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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22303921</pmid><doi>10.1021/tx200540z</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Hydrogen Peroxide - chemistry Molecular Dynamics Simulation Oxidation-Reduction Sulfhydryl Compounds - chemistry |
title | Molecular Basis of the Mechanism of Thiol Oxidation by Hydrogen Peroxide in Aqueous Solution: Challenging the SN2 Paradigm |
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