Li Mengxin, Cong Yalong, Li Yuchen, Zhong Susu, Wang Ran, Li Hao, Duan Lili
School of Physics and Electronics, Shandong Normal University, Jinan, China.
Department of Science and Technology, Shandong Normal University, Jinan, China.
Front Chem. 2019 Jan 29;7:33. doi: 10.3389/fchem.2019.00033. eCollection 2019.
The study of the p53-MDMX/MDM2 binding sites is a research hotspot for tumor drug design. The inhibition of p53-targeted MDMX/MDM2 has become an effective approach in anti-tumor drug development. In this paper, a theoretically rigorous and computationally accurate method, namely, the interaction entropy (IE) method, combined with the polarized protein-specific charge (PPC) force field, is used to explore the difference in the binding mechanism between p53-MDMX and p53-MDM2. The interaction of a 12mer peptide inhibitor (pDIQ), which is similar to p53 in structure, with MDMX/MDM2 is also studied. The results demonstrate that p53/pDIQ with MDM2 generates a stronger interaction than with MDMX. Compared to p53, pDIQ has larger binding free energies with MDMX and MDM2. According to the calculated binding free energies, the differences in the binding free energy among the four complexes that are obtained from the combination of PPC and IE are more consistent with the experimental values than with the results from the combination of the non-polarizable AMBER force field and IE. In addition, according to the decomposition of the binding free energy, the van der Waals (vdW) interactions are the main driving force for the binding of the four complexes. They are also the main source of the weaker binding affinity of p53/pDIQ-MDMX relative to p53/pDIQ-MDM2. Compared with p53-MDMX/MDM2, according to the analysis of the residue decomposition, the predicated total residue contributions are higher in pDIQ-MDMX/MDM2 than in p53-MDMX/MDM2, which explains why pDIQ has higher binding affinity than p53 with MDMX/MDM2. The current study provides theoretical guidance for understanding the binding mechanisms and designing a potent dual inhibitor that is targeted to MDMX/MDM2.
p53-MDMX/MDM2结合位点的研究是肿瘤药物设计的一个研究热点。抑制靶向p53的MDMX/MDM2已成为抗肿瘤药物研发的一种有效方法。本文采用一种理论严谨且计算精确的方法，即相互作用熵（IE）方法，并结合极化蛋白特异性电荷（PPC）力场，来探究p53-MDMX与p53-MDM2之间结合机制的差异。还研究了一种结构与p53相似的12聚体肽抑制剂（pDIQ）与MDMX/MDM2的相互作用。结果表明，p53/pDIQ与MDM2产生的相互作用比与MDMX更强。与p53相比，pDIQ与MDMX和MDM2具有更大的结合自由能。根据计算得到的结合自由能，由PPC和IE结合得到的四种复合物之间结合自由能的差异比由非极化AMBER力场和IE结合得到的结果更符合实验值。此外，根据结合自由能的分解，范德华（vdW）相互作用是四种复合物结合的主要驱动力。它们也是p53/pDIQ-MDMX相对于p53/pDIQ-MDM2结合亲和力较弱的主要来源。与p53-MDMX/MDM2相比，根据残基分解分析，预测的总残基贡献在pDIQ-MDMX/MDM2中高于p53-MDMX/MDM2，这解释了为什么pDIQ与MDMX/MDM2的结合亲和力高于p53。当前的研究为理解结合机制和设计靶向MDMX/MDM2的有效双抑制剂提供了理论指导。
