抑制剂8Q9和8QC与bromodomain结构域蛋白4作用机理的分子动力学研究

Insight into interaction mechanism of inhibitor 8Q9 and 8QC to bromodomain-containing protein 4 by using molecular dynamics simulation

Bromodomain结构域蛋白4(bromodomain-containing protein 4,BRD4)已成为治疗多种疾病药物设计的重要靶标.最近在实验上发现了几种有效的靶向BRD4的抑制剂,但具体的抑制机理尚不清楚.此工作采用分子动力学模拟,动态相关性分析和结合自由能计算研究抑制剂8Q9和8QC与BRD4(1)的结合模式.分子动力学分析表明抑制剂结合对BRD4(1)的结构柔性产生重大影响.同时动态相关性分析进一步表明抑制剂结合极大地改变了BRD4(1)的运动模式.结合自由能计算结果表明范德华相互作用是抑制剂与BRD4(1)结合的主要驱动力.采用基于残基的自由能分解方法评估了分离残基对抑制剂结合的贡献,数据表明氢键相互作用和疏水相互作用是影响抑制剂与BRD4(1)结合的关键因素.本研究有望为设计和开发靶向BRD4的抑制剂提供有意义的理论指导.

Bromodomain-containing protein 4(BRD4) has been employed as a potential target for treating various human diseases. Recently,several effective inhibitors targeting BRD4 have been found in experiments. However,the interaction mechanism of these inhibitors with BRD4 is still lack. In this work,molecular dynamics(MD) simulations,dynamic cross-correlation map(DCCM) and binding free energy calculations were used to study the binding modes of inhibitors 8 Q9 and 8 QC to BRD4(1). Dynamics analysis shows that the presence of inhibitors generates significant impact on the structural flexibility of BRD4(1). The information stemming from DCCM suggests that inhibitor bindings also cause significant changes in movement patterns of BRD4(1). The results of binding free energy calculations show that the van der Waals interactions are the key driving force for the binding of inhibitors to BRD4(1). Residue-based free energy decomposition method was used to reveal the contribution of per residue,and the results indicate that hydrogen bonding interactions and hydrophobic interactions play the key role in bindings of inhibitors to BRD4(1). The results from this work are expected to provide theoretical guidance for design and development of inhibitors targeting BRD4.