Xing Juan, Mei Hu, Huang ShuHeng, Zhang Duo, Pan XianChao
Key Laboratory of Biorheological Science and Technology (Ministry of Education), College of Bioengineering, Chongqing University, Chongqing 400045, China.
Department of Pathophysiology, College of Basic Medical Science, Southwest Medical University, Luzhou, Sichuan 646000, China.
Comput Struct Biotechnol J. 2019 Feb 22;17:319-323. doi: 10.1016/j.csbj.2019.02.008. eCollection 2019.
P-glycoprotein (P-gp) is a multidrug transporter, which harnesses the chemical energy of ATP to power the efflux of diverse chemotherapeutics out of cells and thus contributes to the development of multidrug resistance (MDR) in cancer. It has been proved that the ligand-binding pocket of P-gp is located at the transmembrane domains (TMDs). However, the access of ligands into the binding pocket remains to be elucidated, which definitely hinder the development of P-gp inhibitors. Herein, the access pathways of a well-known substrate rhodamine-123 and a cyclopeptide inhibitor QZ-Leu were characterized by time-independent partial nudged elastic band (PNEB) simulations. The decreasing free energies along the PNEB-optimized access pathway indicated that TM4/6 cleft may be an energetically favorable entrance gate for ligand entry into the binding pocket of P-gp. The results can be reconciled with a range of experimental studies, further corroborating the reliability of the gate revealed by computational simulations. Our atomic level description of the ligand access pathway provides valuable insights into the gating mechanism for drug uptake and transport by P-gp and other multidrug transporters.
P-糖蛋白（P-gp）是一种多药转运蛋白，它利用ATP的化学能量推动多种化疗药物排出细胞，从而导致癌症多药耐药性（MDR）的产生。已证实P-gp的配体结合口袋位于跨膜结构域（TMDs）。然而，配体进入结合口袋的途径仍有待阐明，这无疑阻碍了P-gp抑制剂的开发。在此，通过与时间无关的部分推挤弹性带（PNEB）模拟，对一种著名的底物罗丹明-123和一种环肽抑制剂QZ-Leu的进入途径进行了表征。沿PNEB优化的进入途径自由能降低表明，TM4/6裂隙可能是配体进入P-gp结合口袋的能量有利入口。该结果可与一系列实验研究相吻合，进一步证实了计算模拟所揭示的通道的可靠性。我们对配体进入途径的原子水平描述为P-gp和其他多药转运蛋白摄取和转运药物的通道机制提供了有价值的见解。
