基于蛋白质专一性力场和分子动力学模拟研究细胞周期依赖性蛋白激酶5与Roscovitine衍生物的作用机制

Mechanism of roscovitine derivatives with CDK5 using polarized protein-specific force field and molecular dynamics simulations

本文通过分子对接,将极化的蛋白质专一性电荷(PPC)替换AMBERFF03电荷,利用分子动力学模拟(MD)和结合自由能计算等方法研究3种Roscovitine衍生物抑制剂与细胞周期依赖性蛋白激酶5(CDK5)的相互作用,分析药物与其周围残基之间的氢键作用以及蛋白质极化对静电作用和范德华作用等的影响。模拟结果表明:3种抑制剂与CDK5的结合模式很相似,范德华力对亲和能有较大贡献。但残基分解分析表明Glu81、Cys83和Lys89与抑制剂形成静电相互作用能显著区分3种不同Roscovitine衍生物类抑制剂的生物活性。

Molecular docking,molecular dynamics（ MD） simulations with substituting the standard AMBERFF03 force field using the polarized protein specific charge（ PPC）,and binding free energy analysis were performed to investigate the interaction between three roscovitine derivatives and cyclindependent kinase 5（ CDK5）.The hydrogen bonding interactions between three inhibitors and adjacent residues and the effect of polarization on electrostatic and van der Waals interactions were analyzed and discussed.Results showed that the binding modes of 3 inhibitors were similar with a great contribution of van der Waals interaction on affinity.The energy decomposition analysis indicated that Glu81,Cys83 and Lys89 are the key residues for differentiating the bioactivity of three inhibitors.