Cation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulations

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dc.contributor.authorSalsbury, Alexa M.en
dc.contributor.authorLemkul, Justin A.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2021-07-27T12:35:49Zen
dc.date.available2021-07-27T12:35:49Zen
dc.date.issued2021-06-01en
dc.description.abstractNucleic acid-ion interactions are fundamentally important to the physical, energetic, and conformational properties of DNA and RNA. These interactions help fold and stabilize highly ordered secondary and tertiary structures, such as G-quadruplexes (GQs), which are functionally relevant in telomeres, replication initiation sites, and promoter sequences. The c-kit protooncogene encodes for a receptor tyrosine kinase and is linked to gastrointestinal stromal tumors, mast cell disease, and leukemia. This gene contains three unique GQ-forming sequences that have proposed antagonistic effects on gene expression. The dominant GQ, denoted c-kit1, has been shown to decrease expression of c-kit transcripts, making the c-kit1GQa promising drug target. Toward disease intervention, more information is needed regarding its conformational dynamics and ion binding properties. Therefore, we performed molecular dynamics simulations of the c-kit1 GQ with K+, Na+, Li+, and mixed salt solutions using the Drude-2017 polarizable force field. We evaluated GQ structure, ion sampling, core energetics, ion dehydration and binding, and ion competition and found that each analysis supported the known GQ-ion specificity trend (K+ > Na+ > Li+). We also found that K+ ions coordinate in the tetrad core antiprismatically, whereas Na+ and Li+ align coplanar to guanine tetrads, partially because of their attraction to surrounding water. Further, we showed that K+ occupancy is higher around the c-kit1 GQ and its nucleobases than Na+ and Li+, which tend to interact with backbone and sugar moieties. Finally, we showed that K+ binding to the c-kit1GQ is faster and more frequent than Na+ and Li+. Such descriptions of GQ-ion dynamics suggest the rate of dehydration as the dominant factor for preference of K+ by DNA GQs and provide insight into noncanonical nucleic acids for which little experimental data exist.en
dc.description.notesThis work was supported by the National Institutes of Health (grant R35GM133754), the Thomas F. and Kate Miller Jeffress Memorial Trust (Bank of America, Trustee), U.S. Department of Agriculture National Institute of Food and Agriculture (project number VA-160092), and The American Association of University Women (American Dissertation Fellowship).en
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R35GM133754]; Thomas F. and Kate Miller Jeffress Memorial Trust (Bank of America, Trustee); U.S. Department of Agriculture National Institute of Food and AgricultureUnited States Department of Agriculture (USDA) [VA-160092]; American Association of University Women (American Dissertation Fellowship)en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.bpj.2021.03.022en
dc.identifier.eissn1542-0086en
dc.identifier.issn0006-3495en
dc.identifier.issue11en
dc.identifier.pmid33794153en
dc.identifier.urihttp://hdl.handle.net/10919/104403en
dc.identifier.volume120en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.titleCation competition and recruitment around the c-kit1 G-quadruplex using polarizable simulationsen
dc.title.serialBiophysical Journalen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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