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dc.contributor.authorPeng, Chunte
dc.contributor.authorFedeles, Bogdan I.
dc.contributor.authorSingh, Vipender
dc.contributor.authorLi, Deyu
dc.contributor.authorAmariuta, Tiffany
dc.contributor.authorEssigmann, John M.
dc.contributor.authorTokmakoff, Andrei
dc.date.accessioned2015-09-08T17:14:42Z
dc.date.available2015-09-08T17:14:42Z
dc.date.issued2015-03
dc.date.submitted2014-08
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/98400
dc.description.abstractAntiviral drugs designed to accelerate viral mutation rates can drive a viral population to extinction in a process called lethal mutagenesis. One such molecule is 5,6-dihydro-5-aza-2′-deoxycytidine (KP1212), a selective mutagen that induces A-to-G and G-to-A mutations in the genome of replicating HIV. The mutagenic property of KP1212 was hypothesized to originate from its amino–imino tautomerism, which would explain its ability to base pair with either G or A. To test the multiple tautomer hypothesis, we used 2D IR spectroscopy, which offers subpicosecond time resolution and structural sensitivity to distinguish among rapidly interconverting tautomers. We identified several KP1212 tautomers and found that >60% of neutral KP1212 is present in the enol–imino form. The abundant proportion of this traditionally rare tautomer offers a compelling structure-based mechanism for pairing with adenine. Additionally, the pK[subscript a] of KP1212 was measured to be 7.0, meaning a substantial population of KP1212 is protonated at physiological pH. Furthermore, the mutagenicity of KP1212 was found to increase dramatically at pH <7, suggesting a significant biological role for the protonated KP1212 molecules. Overall, our data reveal that the bimodal mutagenic properties of KP1212 result from its unique shape shifting ability that utilizes both tautomerization and protonation.en_US
dc.description.sponsorshipNational Science Foundation (U.S.) (Grant CHE-1212557)en_US
dc.description.sponsorshipNational Science Foundation (U.S.) (Grant CHE-1414486)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant P30-ES002109)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant P41-EB015871)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Traineeship T32 ES007020)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant CA080024)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (Grant CA26731)en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1415974112en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceNational Academy of Sciences (U.S.)en_US
dc.titleTwo-dimensional IR spectroscopy of the anti-HIV agent KP1212 reveals protonated and neutral tautomers that influence pH-dependent mutagenicityen_US
dc.typeArticleen_US
dc.identifier.citationPeng, Chunte Sam, Bogdan I. Fedeles, Vipender Singh, Deyu Li, Tiffany Amariuta, John M. Essigmann, and Andrei Tokmakoff. “Two-Dimensional IR Spectroscopy of the Anti-HIV Agent KP1212 Reveals Protonated and Neutral Tautomers That Influence pH-Dependent Mutagenicity.” Proceedings of the National Academy of Sciences 112, no. 11 (March 17, 2015): 3229–34.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Center for Environmental Health Sciencesen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistryen_US
dc.contributor.mitauthorPeng, Chunteen_US
dc.contributor.mitauthorFedeles, Bogdan I.en_US
dc.contributor.mitauthorSingh, Vipenderen_US
dc.contributor.mitauthorLi, Deyuen_US
dc.contributor.mitauthorAmariuta, Tiffanyen_US
dc.contributor.mitauthorEssigmann, John M.en_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsPeng, Chunte Sam; Fedeles, Bogdan I.; Singh, Vipender; Li, Deyu; Amariuta, Tiffany; Essigmann, John M.; Tokmakoff, Andreien_US
dc.identifier.orcidhttps://orcid.org/0000-0002-8241-4834
dc.identifier.orcidhttps://orcid.org/0000-0002-2196-5691
mit.licensePUBLISHER_POLICYen_US
mit.metadata.statusComplete


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