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

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-1K131.同时发现,与PD-1K131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.

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

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 predicted 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-1K131 is the only hotspot shared by the two PD-1/mAb complexes. It is also found that key residues of mAbs binding to _D-1K131 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 electrostatic energy. The present work provides important insights for the design of new mAbs targeting PD-1.