Department of Theoretical Chemistry and Biology, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, 10691 Stockholm, Sweden.
Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
J Chem Inf Model. 2020 Mar 23;60(3):1551-1558. doi: 10.1021/acs.jcim.9b00920. Epub 2020 Feb 26.
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.
无规卷曲蛋白（IDPs）通过与伴侣蛋白结合来发挥其功能，这一复杂过程包括偶联的折叠和结合。由于抑制 IDP p53 与其伴侣 MDM2 的结合已成为设计抗癌药物的一种有前途的策略，我们进行了元动力学模拟，以原子细节研究将 IDP p53 与 MDM2 连接起来的偶联折叠和结合过程。我们使用偏置交换元动力学（BE-MetaD）和非频繁元动力学（InMetaD）来估计结合自由能、解结合速率和结合速率。通过分析稳定的中间体，我们揭示了非天然相互作用在 p53-MDM2 结合/解结合过程中所起的作用。我们使用三态模型来描述整个结合/解结合过程，并获得相应的速率常数。我们的工作表明，p53 的结合有利于逐步进行的诱导契合机制。我们的结果有助于深入了解设计 MDM2 抑制剂所需的偶联折叠和结合过程。
