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dc.contributor.authorChakraborty, Debayanen
dc.contributor.authorCollepardo-Guevara, Rosanaen
dc.contributor.authorWales, Daviden
dc.date.accessioned2015-03-31T14:12:50Z
dc.date.available2015-03-31T14:12:50Z
dc.date.issued2014-12-02en
dc.identifier.citationJournal of the American Chemical Society, 2014, 136 (52), pp 18052–18061 DOI: 10.1021/ja5100756en
dc.identifier.issn0002-7863
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/247236
dc.description.abstractRNA hairpins play a pivotal role in a diverse range of cellular functions, and are integral components of ribozymes, mRNA, and riboswitches. However, the mechanistic and kinetic details of RNA hairpin folding, which are key determinants of most of its biological functions, are poorly understood. In this work, we use the discrete path sampling (DPS) approach to explore the energy landscapes of two RNA tetraloop hairpins, and provide insights into their folding mechanisms and kinetics in atomistic detail. Our results show that the potential energy landscapes have a distinct funnel-like bias toward the folded hairpin state, consistent with efficient structure-seeking properties. Mechanistic and kinetic information is analyzed in terms of kinetic transition networks. We find microsecond folding times, consistent with temperature jump experiments, for hairpin folding initiated from relatively compact unfolded states. This process is essentially driven by an initial collapse, followed by rapid zippering of the helix stem in the final phase. Much lower folding rates are predicted when the folding is initiated from extended chains, which undergo longer excursions on the energy landscape before nucleation events can occur. Our work therefore explains recent experiments and coarse-grained simulations, where the folding kinetics exhibit precisely this dependency on the initial conditions.
dc.description.sponsorshipWe are grateful to Dr. David de Sancho, Dr. Yassmine Chebaro, Dr. Guillem Portella, Dr. Chris Whittleston, and Dr. Joanne M. Carr for helpful discussions. We also thank Mr. Boris Fackovec for his comments on an initial version of the manuscript. The work was financially supported by the ERC. D.C. gratefully acknowledges the Cambridge Commonwealth, European and International Trust for financial support.
dc.languageEnglishen
dc.language.isoenen
dc.publisherACS
dc.titleEnergy landscapes, folding mechanisms and kinetics of RNA tetraloop hairpinsen
dc.typeArticle
dc.description.versionThis is the accepted manuscript for a paper published in Journal of the American Chemical Society, 2014, 136 (52), pp 18052–18061 DOI: 10.1021/ja5100756en
prism.endingPage18061
prism.publicationDate2014en
prism.publicationNameJournal of the American Chemical Societyen
prism.startingPage18052
prism.volume52en
dc.rioxxterms.funderERC
rioxxterms.versionofrecord10.1021/ja5100756en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2014-12-02en
dc.contributor.orcidWales, David [0000-0002-3555-6645]
dc.identifier.eissn1520-5126
rioxxterms.typeJournal Article/Reviewen
rioxxterms.freetoread.startdate2015-12-02


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