抑制剂对溴结构域蛋白4的两个溴结构域选择机制的多副本分子动力学模拟和自由能分析  

Selective Mechanism of Inhibitors to Two Bromodomains of BRD4 Revealed by Multiple Replica Molecular Dynamics Simulations and Free Energy Analyses

作　　者：李梦 刘新国[1] 张少龙[1] 孙嘉豪 张庆刚[1] 陈建中[2] Meng Li;Xinguo Liu;Shaolong Zhang;Jiahao Sun;Qinggang Zhang;Jianzhong Chen(School of Physics and Electronics,Shandong Normal University,Jinan 250358,China;Schoolof Science,Shandong Jiaotong University,Jinan 250357,China)

机构地区：[1]山东师范大学物理与电子科学学院,济南250358 [2]山东交通学院理学院,济南250357

出　　处：《Chinese Journal of Chemical Physics》2023年第6期725-739,I0029-I0035,I0057,共23页化学物理学报（英文）

基　　金：supported by the National Natural Science Foundation of China(No.11274205,No.11274206,and No.11504206);Natural Science Foundation of Shandong Province(ZR2022MA016,ZR2020ME231);Key Research and Development Project of Shan-dong province(No.2019GGX102050).

摘　　要：溴结构域蛋白4在细胞周期调节中至关重要,已成为治疗各种癌症的潜在靶标、溴结构域蛋白4包含两个溴结构域,即BD1和BD2.研究表明,选择性地抑制BD1或BD2可能提供更有效的治疗方案.因此,了解抑制剂对BD1和BD2结合的选择性机制对于开发BD1和BD2的高选择性抑制剂至关重要.本文利用多副本分子动力学模拟研究了抑制剂SG3-179、GSK778和GSK620对BD1和BD2的结合选择性.结果显示,BD1比BD2具有更强的结构灵活性,而且BD1和BD2表现出不同的内部动力学.对自由能景观的分析表明,BD1和BD2的构象分布存在明显的差异.结合自由能预测表明,熵变、静电相互作用和范德华相互作用是SG3-179、GSK778和GSK620对BD1和BD2选择性结合的关键因素.单个残基能量贡献的计算表明,(BD1,BD2)中的残基(W81,W374)、(P82,P375)、(Q85,K378)、(V87,V380)、(L92,L385)、(N93,G386)、(L94,L387)、(C136,C429)、(N140,N433)、(K141,P434)、(D144,H437)和(I146,V439)在SG3-179、GSK778和GSK620与BD1和BD2的结合中产生明显的能量差异,它们可以作为开发针对BD1或BD2的高选择性抑制剂的有效靶点.相关信息可为提高抑制剂对BD1和BD2的选择性提供重要的理论指导.Bromodomain-containing protein 4(BRD4)is critical in cell cycle regulation and has emerged as a potential target for treatment of various cancers.BRD4 contains two bromodomains,namely BDl and BD2.Research suggests that selectively inhibiting BDl or BD2 may provide more effective treatment options.Therefore,understanding the selective mechanism of inhibitor binding to BDl and BD2 is essential for development of high selective inhibitors to BDl and BD2.Multiple replica molecular dynamics(MRMD)simulations are utilized to investigate the binding selectivity of inhibitors SG3-179,GSK778,and GSK620 for BDl and BD2.The results show that BDl has stronger structural flexibility than BD2,moreover BDl and BD2 exhibit different internal dynamics.The analyses of free energy landscapes reveal significant differences in the conformational distribution of BDl and BD2.Binding free energy predictions suggest that entropy changes,electrostatic interactions,and van der Waals interactions are key factors in the selective binding of BDl and BD2 by SG3-179,GSK778,and GSK620.The calculations of the energy contributions of individual residues demonstrate that residues(W81,W374),(P82,P375),(Q85,K378),(V87,V380),(192,1385),(N93,G386),(194,1387),(C136,C429),(N140,N433),(K141,P434),(D144,H437)and(1146,V439)corresponding to(BDl,BD2)generate significant energy difference in binding of SG3-179,GSK778,and GSK620 to BDl and BD2,and they can serve as effective targets for development of high selective inhibitors against BDl or BD2.The related information may provide significant theoretical guidance for improving the selectivity of inhibitors for BDl and BD2.

关 键 词：溴结构域 结合选择性 多副本分子动力学模拟 自由能预测 

分 类 号：TQ460.1[化学工程—制药化工]