文献类型：期刊文献

英文题名：Free Energy Profile and Kinetics of Coupled Folding and Binding of the Intrinsically Disordered Protein p53 with MDM2

作者：Zou, Rongfeng[3];Zhou, Yang[3];Wang, Yong[4];Kuang, Guanglin[3];Agren, Hans[3,5];Wu, Junchen[1,2];Tu, Yaoquan[3,5]

机构：[1]East China Univ Sci & Technol, Key Lab Adv Mat, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Inst Fine Chem, Sch Chem & Mol Engn, Shanghai 200237, Peoples R China;[3]KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Theoret Chem & Biol, S-10691 Stockholm, Sweden;[4]Univ Copenhagen, Linderstrom Lang Ctr Prot Sci, Dept Biol, Struct Biol & NMR Lab, DK-2200 Copenhagen N, Denmark;[5]Henan Univ, Coll Chem & Chem Engn, Kaifeng 475004, Henan, Peoples R China

年份：2020

卷号：60

期号：3

起止页码：1551

外文期刊名：JOURNAL OF CHEMICAL INFORMATION AND MODELING

收录：;EI(收录号：20203209005613);WOS:【SCI-EXPANDED(收录号:WOS:000526390800044)】；

基金：R.Z. and Y.Z. thank the China Scholarship Council for financial support. Y.W. was supported by the BRAINSTRUC initiative from the Lundbeck Foundation. The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC) at PDC, as supported by the contract "Multiphysics Modelling" SNIC 201912-41.

语种：英文

外文关键词：Free energy - Binding energy - Proteins

摘要：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.