Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations
cam.issuedOnline | 2017-10-23 | |
cam.orpheus.success | Thu Jan 30 10:20:11 GMT 2020 - The item has an open VoR version. | |
datacite.issupplementedby.doi | 10.17617/3.x | |
dc.contributor.author | Paul, F | |
dc.contributor.author | Wehmeyer, C | |
dc.contributor.author | Abualrous, ET | |
dc.contributor.author | Wu, H | |
dc.contributor.author | Crabtree, MD | |
dc.contributor.author | Schöneberg, J | |
dc.contributor.author | Clarke, J | |
dc.contributor.author | Freund, C | |
dc.contributor.author | Weikl, TR | |
dc.contributor.author | Noé, F | |
dc.contributor.orcid | Crabtree, Michael [0000-0003-1466-4011] | |
dc.contributor.orcid | Clarke, Jane [0000-0002-7921-900X] | |
dc.date.accessioned | 2017-10-04T16:13:59Z | |
dc.date.available | 2017-10-04T16:13:59Z | |
dc.date.issued | 2017-10-23 | |
dc.description.abstract | Understanding 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.sponsorship | Funding 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.identifier.doi | 10.17863/CAM.13655 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/267726 | |
dc.language.iso | eng | |
dc.publisher | Springer Nature | |
dc.publisher.url | http://dx.doi.org/10.1038/s41467-017-01163-6 | |
dc.rights | Attribution 4.0 International | |
dc.rights | Attribution 4.0 International | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Biological physics | |
dc.subject | Chemical physics | |
dc.subject | Computational biophysics | |
dc.subject | Reaction kinetics and dynamics | |
dc.title | Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations | |
dc.type | Article | |
dcterms.dateAccepted | 2017-08-22 | |
prism.number | 1095 | |
prism.publicationDate | 2017 | |
prism.publicationName | Nature Communications | |
prism.volume | 8 | |
pubs.funder-project-id | Wellcome Trust (095195/Z/10/Z) | |
pubs.funder-project-id | BBSRC (1348064) | |
rioxxterms.licenseref.startdate | 2017-10-23 | |
rioxxterms.licenseref.uri | http://creativecommons.org/licenses/by/4.0/ | |
rioxxterms.type | Journal Article/Review | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1038/s41467-017-01163-6 |
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