Understanding the structural and energetic basis of PD-1 and monoclonal antibodies bound to PD-L1: A molecular modeling perspective

• Published in: Biochimica et biophysica acta. General subjects Vol. 1862; no. 3; pp. 576 - 588
• Main Authors: Shi, Danfeng, Zhou, Shuangyan, Liu, Xuewei, Zhao, Chenxi, Liu, Huanxiang, Yao, Xiaojun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2018
• Subjects: Amino Acid Motifs; Amino Acids - chemistry; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - metabolism; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents, Immunological - chemistry; Antineoplastic Agents, Immunological - metabolism; B7-H1 Antigen - chemistry; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; B7-H1 Antigen - metabolism; Crystallography, X-Ray; Drug Design; Humans; Ligands; Models, Molecular; Molecular Dynamics Simulation; Monoclonal antibody; Mutagenesis, Site-Directed; PD-1; PD-L1; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Programmed Cell Death 1 Receptor - chemistry; Programmed Cell Death 1 Receptor - metabolism; Protein Conformation; Protein Interaction Mapping; Virtual alanine scanning mutagenesis; PD-L1; Virtual alanine scanning mutagenesis; Monoclonal antibody; Molecular dynamics simulation; PD-1
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.11.022

The inhibitors blocking the interaction between programmed cell death protein 1(PD-1) and programmed death-ligand 1(PD-L1) can activate the immune response of T cell and eliminate cancer cells. The crystallographic studies have provided structural insights of the interactive interfaces between PD-L1 and its protein ligands. However, the hotspot residues on PD-L1 as well as structural and energetic basis for different protein ligands still need to be further investigated. Molecular modeling methods including molecular dynamics simulation, per-residue free energy decomposition, virtual alanine scanning mutagenesis and residue-residue contact analysis were used to qualitatively and quantitatively analyze the interactions between PD-L1 and different protein ligands. The results of virtual alanine scanning mutagenesis suggest that Y56, Q66, M115, D122, Y123, R125 are the hotspot residues on PD-L1. The residue-residue contact analysis further shows that PD-1 interacts with PD-L1 mainly by F and G strands while monoclonal antibodies like avelumab and BMS-936559 mainly interact with PD-L1 by CDR2 and CDR3 loops of the heavy chain. A structurally similar β-hairpin peptide with 13 or 14 residues was extracted from each protein ligand and these β-hairpin peptides were found tightly binding to the putative hotspot residues on PD-L1. This study recognizes the hotspot residues on PD-L1 and uncovers the common structural and energetic basis of different protein ligands binding to PD-L1. These results will be valuable for the design of small molecule or peptide inhibitors targeting on PD-L1. The hotspot residues on PD-L1 and the common structural and energetic basis of different protein ligands were identified by molecular dynamics simulations. [Display omitted] •The blockage of interaction between PD-1 and PD-L1 effectively fights against malignant neoplasms.•Multiple analytical methods are used to evaluate the interfacial interactions between PD-L1 and its protein ligands.•Structurally similar β-hairpin domains were found tightly binding to the recognized hotspot residues on PD-L1.