Base pair dynamics, electrostatics, and thermodynamics at the LTR-III quadruplex:duplex junction

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dc.contributor.authorMichel, Haley M.en
dc.contributor.authorLemkul, Justin A.en
dc.date.accessioned2025-01-08T18:35:50Zen
dc.date.available2025-01-08T18:35:50Zen
dc.date.issued2024-04-04en
dc.description.abstractG-quadruplexes (GQs) play key regulatory roles within the human genome and have also been identified to play similar roles in other eukaryotes, bacteria, archaea, and viruses. Human immunodeficiency virus 1, the etiological agent of acquired immunodeficiency syndrome, can form two GQs in its long terminal repeat (LTR) promoter region, each of which act to regulate viral gene expression in opposing manners. The major LTR GQ, called LTR-III, is a distinct hybrid GQ containing a 12-nucleotide duplex loop attached to the quadruplex motif. The resulting quadruplex:duplex junction (QDJ) has been hypothesized to serve as a selective drug targeting site. To better understand the dynamics of this QDJ, we performed conventional and enhanced-sampling molecular dynamics simulations using the Drude-2017 force field. We observed unbiased and reversible formation of additional base pairs in the QDJ, between Ade4:Thy14 and Gua3:Thy14. Both base pairs were electrostatically favored, but geometric constraints within the junction may drive the formation of, and preference for, the Ade4:Thy14 base pair. Finally, we demonstrated that the base pairs are separated only by small energy barriers that may enable transitions between both base-paired states. Together, these simulations provide new insights into the dynamics, electrostatics, and thermodynamics of the LTR-III QDJ.en
dc.description.versionAccepted versionen
dc.format.extentPages 1129-1138en
dc.format.extent10 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.bpj.2024.03.042en
dc.identifier.eissn1542-0086en
dc.identifier.issn0006-3495en
dc.identifier.issue9en
dc.identifier.orcidLemkul, Justin [0000-0001-6661-8653]en
dc.identifier.otherS0006-3495(24)00244-3 (PII)en
dc.identifier.pmid38576161en
dc.identifier.urihttps://hdl.handle.net/10919/123963en
dc.identifier.volume123en
dc.language.isoenen
dc.publisherCell Pressen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/38576161en
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subject.meshHIV Long Terminal Repeaten
dc.subject.meshBase Pairingen
dc.subject.meshThermodynamicsen
dc.subject.meshG-Quadruplexesen
dc.subject.meshStatic Electricityen
dc.subject.meshMolecular Dynamics Simulationen
dc.titleBase pair dynamics, electrostatics, and thermodynamics at the LTR-III quadruplex:duplex junctionen
dc.title.serialBiophysical Journalen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2024-03-29en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Agriculture & Life Sciencesen
pubs.organisational-groupVirginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen

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