分子动力学和丙氨酸变异研究MDM2与抑制剂P4的结合模式

抑制p53-MDM2相互作用已经成为癌症治疗的新途径. 采用分子动力学模拟和MM-PBSA(molecular mechanics-Possion-Boltzmann surface area)方法研究了肽类抑制剂P4与MDM2的结合模式. 研究表明P4与MDMD2疏水性裂缝的范德华作用是抑制剂结合的主导力量。采用丙氨酸变异计算研究了P4与MDM2的作用热区. 结果表明残基Lys51, Leu54, Leu57, Ile61, Met62, Tyr67, Gln72, His73, Val93, His96和Ile99的丙氨酸变异导致了范德华作用的降低, 而对极性相互作用几乎没有产生影响, 同时也证明这些残基处于P4与MDM2作用表面的热区, 对抑制剂的结合有重要贡献, 这能为抗癌药物的设计提供理论上的指导. 关键词：分子动力学; 丙氨酸变异; MM-PBSA; p53-MDM2相互作用

Insight into binding mode of inhibitor P4 to MDM2 based on molecular dynamics and alanine mutation calculations

Inhibition of p53-MDM2 interaction has been a new approach curing cancers. Molecular dynamics simulation coupled with molecular mechanics-Poisson-Boltzmann surface area (MM-PBAS) method was performed to study the binding mode of inhibitor P4 to MDM2. The results show that van der Waals interactions of P4 with the hydrophobic cleft of MDM2 drive inhibitor binding. Computational alanine scanning mutagensis was adopted to explore the hot spots of P4-MDM2 interaction. The results suggest that alanine mutations of residues Lys51, Leu54, Leu57, Ile61, Met62, Tyr67, Gln72, His73, Val93, His96 and Ile99 from MDM2 lead to a big decrease in van der Waals energy, but hardly produce effects on polar interactions. At the same time, this result also proves that these residues locate in the hot spots of interaction surface between P4 and MDM2, and provide important contributions to inhibitor binding. This study can provide significant helps for anti-cancer drug designs.