Residue-specific binding mechanisms of PD-L1 to its monoclonal antibodies by computational alanine scanning

Wei Wen, Dading Huang, Jingxiao Bao, John Z.H. Zhang

Research output: Contribution to journalArticlepeer-review


Programmed cell death 1 receptor (PD-1) on the surface of T cells and its ligand 1 (PD-L1) are immune checkpoint proteins. Treating cancer patients with inhibitors blocking this checkpoint has significantly prolonged the survival rate of patients. In this study, we examined several monoclonal antibodies (mAbs) of PD-L1 and studied their detailed binding mechanism to PD-L1. An efficient computational alanine scanning method was used to perform quantitative analysis of hotspot residues that are important for PD-1/PD-L1 binding. A total of five PD-L1/mAb complexes were investigated and hotspots on both PD-L1 and mAbs were predicted. Our result shows that PD-L1M115 and PD-L1Y123 are two relatively important hotspots in all the five PD-L1/mAb binding complexes. It is also found that the important residues of mAbs binding to PD-L1M115 and PD-L1Y123 are similar to each other. The computational alanine scanning result is compared to the experimental measurements that are available for two of the mAbs (KN035 and atezolizumab). The calculated alanine scanning result is in good agreement with the experimental data with a correlation coefficient of 0.87 for PD-L1/KN035 and 0.6 for PD-L1/atezolizumab. Our computation found more hotspots on PD-L1 in the PD-L1/KN035 complex than those in the PD-L1/atezolizumab system, indicating stronger binding affinity in the former than the latter, which is in good agreement with the experimental finding. The present work provides important insights for the design of new mAbs targeting PD-L1.

Original languageEnglish (US)
Pages (from-to)15591-15600
Number of pages10
JournalPhysical Chemistry Chemical Physics
Issue number29
StatePublished - Aug 7 2021


  • Alanine/chemistry
  • Amino Acid Sequence
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized/chemistry
  • B7-H1 Antigen/chemistry
  • Humans
  • Molecular Dynamics Simulation
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Structure-Activity Relationship
  • Thermodynamics

ASJC Scopus subject areas

  • General Physics and Astronomy
  • Physical and Theoretical Chemistry


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