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PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations

College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Chengdu University, Chengdu 610106, China
Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
College of Mathematics and Informatics, South China Agricultural University, Guangzhou 510642, China
Laboratory of tumor targeted and immune therapy, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2018, 19(7), 1984;
Received: 1 June 2018 / Revised: 2 July 2018 / Accepted: 4 July 2018 / Published: 7 July 2018
(This article belongs to the Section Molecular Biophysics)
PDF [7220 KB, uploaded 7 July 2018]


The anti-PD-L1 monoclonal antibody (mAb) targeting PD-1/PD-L1 immune checkpoint has achieved outstanding results in clinical application and has become one of the most popular anti-cancer drugs. The mechanism of molecular recognition and inhibition of PD-L1 mAbs is not yet clear, which hinders the subsequent antibody design and modification. In this work, the trajectories of PD-1/PD-L1 and nanobody/PD-L1 complexes were obtained via comparative molecular dynamics simulations. Then, a series of physicochemical parameters including hydrogen bond, dihedral angle distribution, pKa value and binding free energy, and so forth, were all comparatively analyzed to investigate the recognition difference between PD-L1 and PD-1 and nanobody. Both LR113 (the amino acid residues in PD-L1 are represented by the lower left sign of L) and LR125 residues of PD-L1 undergo significant conformational change after association with mAbs, which dominates a strong electrostatic interaction. Solvation effect analysis revealed that solvent-water enhanced molecular recognition between PD-L1 and nanobody. By combining the analyses of the time-dependent root mean squared fluctuation (RMSF), free energy landscape, clustering and energy decomposition, the potential inhibition mechanism was proposed that the nanobody competitively and specifically bound to the β-sheet groups of PD-L1, reduced the PD-L1’s flexibility and finally blocked the formation of PD-1/PD-L1 complex. Based on the simulation results, site-directed mutagenesis of ND99 (the amino acid residues in Nano are displayed by the lower left sign of N) and NQ116 in the nanobody may be beneficial for improving antibody activity. This work offers some structural guidance for the design and modification of anticancer mAbs based on the structure of the PD-1/PD-L1 complex. View Full-Text
Keywords: PD-1/PD-L1; monoclonal antibody; MD simulation; inhibitory mechanism; antibody design PD-1/PD-L1; monoclonal antibody; MD simulation; inhibitory mechanism; antibody design

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Sun, X.; Yan, X.; Zhuo, W.; Gu, J.; Zuo, K.; Liu, W.; Liang, L.; Gan, Y.; He, G.; Wan, H.; Gou, X.; Shi, H.; Hu, J. PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations. Int. J. Mol. Sci. 2018, 19, 1984.

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