Zhou Zhong-Xing, Zhang Hong-Xing, Zheng Qing-Chuan
Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun, China.
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, China.
Front Chem. 2021 Nov 9;9:783444. doi: 10.3389/fchem.2021.783444. eCollection 2021.
The new cancer immunotherapy has been carried out with an almost messianic zeal, but its molecular basis remains unclear due to the complexity of programmed death ligand 1 (PD-L1) dimerization. In this study, a new and integral multiple dimerization-modes transformation process of PD-L1s (with a new PD-L1 dimerization mode and a new transformation path discovered) and the corresponding mechanism are predicted using theoretical and computational methods. The results of the state analysis show that 5 stable binding states exist in system. A generalized inter-state transformation rate (GITR) theory is also proposed in such multiple-states self-assembly system to explore the kinetic characteristics of inter-state transformation. A "drug insertion" path was identified as the dominant path of the PD-L1 dimerization-modes transformation. Above results can provide supports for both the relative drug design and other multiple-states self-assembly system from the theoretical chemistry perspective.
新的癌症免疫疗法已带着近乎救世主般的热情开展起来，但由于程序性死亡配体1（PD-L1）二聚化的复杂性，其分子基础仍不清楚。在本研究中，使用理论和计算方法预测了PD-L1s新的、完整的多二聚化模式转变过程（发现了一种新的PD-L1二聚化模式和一条新的转变路径）及其相应机制。状态分析结果表明，系统中存在5种稳定结合状态。还在此多状态自组装系统中提出了广义态间转化率（GITR）理论，以探索态间转变的动力学特征。一条“药物插入”路径被确定为PD-L1二聚化模式转变的主导路径。上述结果可从理论化学角度为相关药物设计及其他多状态自组装系统提供支持。
