School of Physics and Material Science, Shanghai Engineering Research Center of Molecular Therapeutics & New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
NYU-ECNU Center for Computational Chemistry at NYU Shanghai, Shanghai 200062, China.
J Comput Chem. 2019 Apr 5;40(9):1045-1056. doi: 10.1002/jcc.25592. Epub 2018 Dec 14.
The recently developed MM/GBSA_IE method is applied to computing hot and warm spots in p53/PMI-MDM2/MDMX protein-protein interaction systems. Comparison of the calculated hot (>2 kcal/mol) and warm spots (>1 kcal/mol) in P53 and PMI proteins interacting with MDM2 and MDMX shows a good quantitative agreement with the available experimental data. Further, our calculation predicted hot spots in MDM2 and MDMX proteins in their interactions with P53 and PMI and they help elucidate the interaction mechanism underlying this important PPI system. In agreement with the experimental result, the present calculation shows that PMI has more hot and warm spots and binds stronger to MDM2/MDMX. The analysis of these hot and warm spots helps elucidate the fundamental difference in binding between P53 and PMI to the MDM2/MDMX systems. Specifically, for p53/PMI-MDM2 systems, p53 and PMI use essentially the same residues (L54, I61, Y67, Q72, V93, H96, and I99) of MDM2 for binding. However, PMI enhanced interactions with residues L54, Y67, and Q72 of MDM2. For the p53/PMI-MDMX system, p53 and PMI use similar residues (M53, I60, Y66, Q71, V92, and Y99) of MDMX for binding. However, PMI exploited three extra residues (M61, K93, and L98) of MDMX for enhanced binding. In addition, PMI enhanced interaction with four residues (M53, Y66, Q71, and Y99) of MDMX. These results gave quantitative explanation on why the binding affinities of PMI-MDM2/MDMX interactions are stronger than that of p53-MDM2/MDMX although their binding modes are similar. © 2018 Wiley Periodicals, Inc.
最近开发的 MM/GBSA_IE 方法被应用于计算 p53/PMI-MDM2/MDMX 蛋白-蛋白相互作用系统中的热点和温点。比较与 MDM2 和 MDMX 相互作用的 P53 和 PMI 蛋白中计算出的热点（>2kcal/mol）和温点（>1kcal/mol）与现有实验数据有很好的定量一致性。此外，我们的计算还预测了 MDM2 和 MDMX 蛋白与其与 P53 和 PMI 相互作用中的热点，这有助于阐明这个重要的 PPI 系统的相互作用机制。与实验结果一致，本计算表明 PMI 具有更多的热点和温点，并且与 MDM2/MDMX 的结合更强。对这些热点和温点的分析有助于阐明 P53 和 PMI 与 MDM2/MDMX 系统结合的基本差异。具体而言，对于 p53/PMI-MDM2 系统，p53 和 PMI 基本上使用 MDM2 的相同残基（L54、I61、Y67、Q72、V93、H96 和 I99）进行结合。然而，PMI 增强了与 MDM2 的残基 L54、Y67 和 Q72 的相互作用。对于 p53/PMI-MDMX 系统，p53 和 PMI 用 MDMX 的相似残基（M53、I60、Y66、Q71、V92 和 Y99）进行结合。然而，PMI 利用 MDMX 的三个额外残基（M61、K93 和 L98）进行增强结合。此外，PMI 增强了与 MDMX 的四个残基（M53、Y66、Q71 和 Y99）的相互作用。这些结果定量解释了为什么尽管结合模式相似，但 PMI-MDM2/MDMX 相互作用的结合亲和力强于 p53-MDM2/MDMX。 © 2018 威立出版社
