Free energy landscape for the binding process of Huperzine A to acetylcholinesterase

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dc.citation.journalTitlePNAS Early Editionen_US
dc.contributor.authorBai, Fangen_US
dc.contributor.authorXu, Yechunen_US
dc.contributor.authorChen, Jingen_US
dc.contributor.authorLiu, Qiufengen_US
dc.contributor.authorGu, Junfengen_US
dc.contributor.authorWang, Xichengen_US
dc.contributor.authorMa, Jianpengen_US
dc.contributor.authorLi, Honglinen_US
dc.contributor.authorOnuchic, José N.en_US
dc.contributor.authorJiang, Hualiangen_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2013-03-15T18:00:55Zen_US
dc.date.available2014-03-19T05:10:03Zen_US
dc.date.issued2012en_US
dc.description.abstractDrug-target residence time (t = 1/koff, where koff is the dissociation rate constant) has become an important index in discovering betteror best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, koff and activation free energy of dissociation (ΔG≠ off). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated.We applied this method to simulate the binding event of the anti-Alzheimer’s disease drug (−)−Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/ mol. The method also provides atomic resolution information for the (−)−Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect thismethodology to be widely applicable to drug discovery and development.en_US
dc.embargo.terms1 yearen_US
dc.identifier.citationBai, Fang, Xu, Yechun, Chen, Jing, et al.. "Free energy landscape for the binding process of Huperzine A to acetylcholinesterase." <i>PNAS Early Edition,</i> (2012) National Academy of Sciences: http://dx.doi.org/10.1073/pnas.1301814110.en_US
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.1301814110en_US
dc.identifier.urihttps://hdl.handle.net/1911/70688en_US
dc.language.isoengen_US
dc.publisherNational Academy of Sciencesen_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.subject.keywordthermodynamicsen_US
dc.subject.keywordflexible dockingen_US
dc.subject.keywordmetastable statesen_US
dc.subject.keywordtransition statesen_US
dc.titleFree energy landscape for the binding process of Huperzine A to acetylcholinesteraseen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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