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Free Energy Profile and Kinetics of Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-1988-7898
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-4167-6413
Univ Copenhagen, Linderstrom Lang Ctr Prot Sci, Dept Biol, Struct Biol & NMR Lab, DK-2200 Copenhagen N, Denmark..ORCID iD: 0000-0001-9156-0377
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-3138-820X
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2020 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 60, no 3, p. 1551-1558Article in journal (Refereed) Published
Abstract [en]

Intrinsically disordered proteins (IDPs) exert their functions by binding to partner proteins via a complex process that includes coupled folding and binding. Because inhibiting the binding of the IDP p53 to its partner MDM2 has become a promising strategy for the design of anticancer drugs, we carried out metadynamics simulations to study the coupled folding and binding process linking the IDP p53 to MDM2 in atomic detail. Using bias-exchange metadynamics (BE-MetaD) and infrequent metadynamics (InMetaD), we estimated the binding free energy, the unbinding rate, and the binding rate. By analyzing the stable intermediates, we uncovered the role non-native interactions played in the p53-MDM2 binding/unbinding process. We used a three-state model to describe the whole binding/unbinding process and to obtain the corresponding rate constants. Our work shows that the binding of p53 favors an induced-fit mechanism which proceeds in a stepwise fashion. Our results can be helpful for gaining an in-depth understanding of the coupled folding and binding process needed for the design of MDM2 inhibitors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2020. Vol. 60, no 3, p. 1551-1558
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Biological Sciences
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URN: urn:nbn:se:kth:diva-272941DOI: 10.1021/acs.jcim.9b00920ISI: 000526390800044PubMedID: 32053358Scopus ID: 2-s2.0-85082147510OAI: oai:DiVA.org:kth-272941DiVA, id: diva2:1431383
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QC 20200520

Available from: 2020-05-20 Created: 2020-05-20 Last updated: 2020-05-20Bibliographically approved

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Zou, RongfengZhou, YangGuanglin, KuangÅgren, HansTu, Yaoquan

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