抑制剂PMI与MDM2结合模式的分子动力学研究

摘要

p53-MDM2相互作用已经成为治疗癌症药物设计的重要靶标.采用分子动力学模拟和MM-PBSA方法计算了肽类抑制剂PMI与MDM2的绝对结合自由能,通过基于残基的自由能分解方法计算了MDM2的各残基与PMI的相互作用.结果表明:CH-π、CH-CH和π-π相互作用驱动了PMI在MDM2疏水性裂缝中的结合；相关矩阵的计算表明PMI在一定程度上诱导了MDM2内部的相关运动.%The p53-MDM2 interaction has been an important target of anti-cancer drug design.Molecular dynamics simulations coupled with molecular mechanics/Poisson Boltzmann surface area method (MM-PBSA) are performed to calculate the absolute binding free energies of peptide inhibitor PMI.Residue-based free energy decomposition method is adopted to compute the interactions of separate residues of MDM2 with PMI.The results prove that the CH-π,CH-CH and π-πinteractions drive the binding of the inhibitor PMI in the hydrophobic cleft of MDM2.The calculation of cross-correlation matrix shows that PMI results in the correlation motion in MDM2.The study will provide important dynamic information for anti-cancer drug designs.