PD-1与单克隆抗体残基特异性结合机制的计算丙氨酸扫描研究  

Residue Specific Binding Mechanisms of PD-1 to Its Monoclonal Antibodies by Computational Alanine Scanning

作　　者：温炜 黄达锭 鲍劲霄 张增辉 WEN Wei;HUANG Dading;BAO Jingxiao;ZHANG John ZH(Shanghai Engineering Research Center of Molecular Therapeutics&New Drug Development,Shanghai Key Laboratory of Green Chemistry&Chemical Process,School of Chemistry and Molecular Engineering,East China Normal University,Shanghai 200062,China;NYU-ECNU Center for Computational Chemistry at NYU Shanghai,Shanghai 200062,China;Department of Chemistry,New York University,NY 10003,USA)

机构地区：[1]华东师范大学化学与分子工程学院,上海绿色化学与化工过程重点实验室,上海分子治疗与新药开发工程研究中心,上海200062 [2]上海纽约大学计算化学联合研究中心,上海200062 [3]美国纽约大学化学系,纽约10003

出　　处：《高等学校化学学报》2021年第7期2161-2169,共9页Chemical Journal of Chinese Universities

基　　金：国家重点研发计划项目(批准号:2016YFA0501700);国家自然科学基金重大研究计划培育项目(批准号:91753103);国家自然科学基金重点项目(批准号:21933010)资助.

摘　　要：通过分子动力学模拟检测了2种程序性细胞死亡蛋白(PD-1)/单克隆抗体(Pembrolizumab和Nivolumab)复合物,并使用高效的计算丙氨酸扫描方法预测了单抗与PD-1的结合热点,将它们与对PD-1/PD-L1结合重要的热点残基进行对比分析.结果显示,Pembrolizumab以类似于PD-L1的方式与PD-1结合,而Nivolumab则以不同的方式与PD-1结合.2个PD-1/mAb复合物中共有的热点只有_(PD-1)K131.同时发现,与_(PD-1)K131结合的单抗的关键残基通常都受范德华(vdW)能量控制.2种单克隆抗体上热点的自由能贡献都以vdW能量为主,这表明在下一代PD-1新抗体的设计中需要提高静电型热点残基的数量.Molecular dynamics simulations were conducted on two PD-1/monoclonal antibody(pembrolizu-mab,nivolumab)complexes separately.The binding hotspots of the monoclonal antibody(mAb)and PD-1 were predicted by using efficient computational alanine scanning method.The comparation between the pre⁃dicted hotspots and the important residues in PD-1/PD-L1 complex shows that pembrolizumab combines with PD-1 in a way similar to PD-L1,while nivolumab combines with PD-1 in a more different way by N-loop._(PD-1)K131 is the only hotspot shared by the two PD-1/mAb complexes.It is also found that key residues of mAbs binding to_(D-1)K131 are similarly dominated by van der Waals(vdW)energy.Furthermore,hotspots on both the monoclonal antibodies are dominated by vdW energy,indicating a demand to improve the contributions of elec⁃trostatic energy.The present work provides important insights for the design of new mAbs targeting PD-1.

关 键 词：程序性细胞死亡蛋白 丙氨酸扫描计算 单克隆抗体 分子力学广义波恩表面积 相互作用熵 

分 类 号：O643[理学—物理化学] O642[理学—化学]