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dc.contributor.authorStadlbauer, Petren
dc.contributor.authorMazzanti, Liubaen
dc.contributor.authorCragnolini, Tristanen
dc.contributor.authorWales, Daviden
dc.contributor.authorDerreumaux, Philippeen
dc.contributor.authorPasquali, Samuelaen
dc.contributor.authorŠponer, Jiříen
dc.date.accessioned2019-02-15T11:11:01Z
dc.date.available2019-02-15T11:11:01Z
dc.date.issued2016-12en
dc.identifier.issn1549-9618
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/289442
dc.description.abstractG-quadruplexes are the most important noncanonical DNA architectures. Many quadruplex-forming sequences, including the human telomeric sequence d(GGGTTA)n, have been investigated due to their implications in cancer and other diseases, and because of their potential in DNA-based nanotechnology. Despite the availability of atomistic structural studies of folded G-quadruplexes, their folding pathways remain mysterious, and mutually contradictory models of folding coexist in the literature. Recent experiments convincingly demonstrated that G-quadruplex folding often takes days to reach thermodynamic equilibrium. Based on atomistic simulations of diverse classes of intermediates in G-quadruplex folding, we have suggested that the folding is an extremely multipathway process combining a kinetic partitioning mechanism with conformational diffusion. However, complete G-quadruplex folding is far beyond the time scale of atomistic simulations. Here we use high-resolution coarse-grained simulations to investigate potential unfolding intermediates, whose structural dynamics are then further explored with all-atom simulations. This multiscale approach indicates how various pathways are interconnected in a complex network. Spontaneous conversions between different folds are observed. We demonstrate the inability of simple order parameters, such as radius of gyration or the number of native H-bonds, to describe the folding landscape of the G-quadruplexes. Our study also provides information relevant to further development of the coarse-grained force field.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Chemical Society (ACS)
dc.subjectTelomereen
dc.subjectHumansen
dc.subjectTemperatureen
dc.subjectNucleic Acid Conformationen
dc.subjectKineticsen
dc.subjectThermodynamicsen
dc.subjectG-Quadruplexesen
dc.subjectInverted Repeat Sequencesen
dc.subjectMolecular Dynamics Simulationen
dc.titleCoarse-Grained Simulations Complemented by Atomistic Molecular Dynamics Provide New Insights into Folding and Unfolding of Human Telomeric G-Quadruplexes.en
dc.typeArticle
prism.endingPage6097
prism.issueIdentifier12en
prism.publicationDate2016en
prism.publicationNameJournal of chemical theory and computationen
prism.startingPage6077
prism.volume12en
dc.identifier.doi10.17863/CAM.36691
dcterms.dateAccepted2016-10-21en
rioxxterms.versionofrecord10.1021/acs.jctc.6b00667en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2016-12en
dc.contributor.orcidCragnolini, Tristan [0000-0001-6917-7056]
dc.contributor.orcidWales, David [0000-0002-3555-6645]
dc.contributor.orcidŠponer, Jiří [0000-0001-6558-6186]
dc.identifier.eissn1549-9626
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idEPSRC (EP/N035003/1)


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