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dc.contributor.authorPaul, F
dc.contributor.authorWehmeyer, C
dc.contributor.authorAbualrous, ET
dc.contributor.authorWu, H
dc.contributor.authorCrabtree, MD
dc.contributor.authorSchöneberg, J
dc.contributor.authorClarke, J
dc.contributor.authorFreund, C
dc.contributor.authorWeikl, TR
dc.contributor.authorNoé, F
dc.date.accessioned2017-10-04T16:13:59Z
dc.date.available2017-10-04T16:13:59Z
dc.date.issued2017-10-23
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/267726
dc.description.abstractUnderstanding and control of structures and rates involved in protein-ligand binding are es- sential for drug design. Unfortunately, atomistic molecular dynamics (MD) simulations cannot di- rectly sample the excessively long residence and rearrangement times of tightly binding complexes. Here we exploit the recently developed multi-ensemble Markov model framework to compute full protein-peptide kinetics of the oncoprotein fragment 25−109Mdm2 and the nano-molar inhibitor peptide PMI. Using this system, we report, for the first time, direct estimates of kinetics beyond the seconds timescales using simulations of an all-atom MD model, with high accuracy and pre- cision. These results only require explicit simulations on the sub-milliseconds timescale and are tested against existing mutagenesis data and our own experimental measurements of the dissoci- ation and association rates. The full kinetic model reveals an overall downhill but rugged binding funnel with multiple pathways. The overall strong binding arises from a variety of conformations with different hydrophobic contact surfaces that interconvert on the milliseconds timescale.
dc.description.sponsorshipFunding is acknowledged by European Commission (ERC StG “pcCells” to F.N.), Deutsche Forschungsgemeinschaft (SFB 1114/C3, SFB 740/D7, and TRR 186/A12 to F.N. and SFB 1114/A4 to F.N. and T.W.). J.C. is a Wellcome Trust Senior Research Fellow (WT 095195MA). J.S. is a Marie Sklodowska-Curie Internationally outgoing fellow. M.D.C. is supported by a Biotechnology and Biological Sciences Research Council (BBSRC) studentship.
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBiological physics
dc.subjectChemical physics
dc.subjectComputational biophysics
dc.subjectReaction kinetics and dynamics
dc.titleProtein-peptide association kinetics beyond the seconds timescale from atomistic simulations
dc.typeArticle
prism.number1095
prism.publicationDate2017
prism.publicationNameNature Communications
prism.volume8
dc.identifier.doi10.17863/CAM.13655
dcterms.dateAccepted2017-08-22
rioxxterms.versionofrecord10.1038/s41467-017-01163-6
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2017-10-23
dc.contributor.orcidCrabtree, Michael [0000-0003-1466-4011]
dc.contributor.orcidClarke, Jane [0000-0002-7921-900X]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (095195/Z/10/Z)
pubs.funder-project-idBBSRC (1348064)
cam.issuedOnline2017-10-23
datacite.issupplementedby.doi10.17617/3.x
cam.orpheus.successThu Jan 30 10:20:11 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International