Computational analysis of hot spots and binding mechanism in the PD-1/PD-L1 interaction.

Programmed cell death protein-1 (PD-1) is an important immunological checkpoint and plays a vital role in maintaining the peripheral tolerance of the human body by interacting with its ligand PD-L1. The overexpression of PD-L1 in tumor cells induces local immune suppression and helps the tumor cells to evade the endogenous anti-tumor immunity. Developing monoclonal antibodies against the PD-1/PD-L1 protein-protein interaction to block the PD-1/PD-L1 signaling pathway has demonstrated superior anti-tumor efficacy in a variety of solid tumors and has made a profound impact on the field of cancer immunotherapy in recent years. Although the X-ray crystal structure of the PD-1/PD-L1 complex has been solved, the detailed binding mechanism of the PD-1/PD-L1 interaction is not fully understood from a theoretical point of view. In this study, we performed computational alanine scanning on the PD-1/PD-L1 complex to quantitatively identify the hot spots in the PD-1/PD-L1 interaction and characterize its binding mechanisms at the atomic level. To the best of our knowledge, this is the first time that theoretical calculations have been used to systematically and quantitatively predict the hot spots in the PD-1/PD-L1 interaction. We hope that the predicted hot spots and the energy profile of the PD-1/PD-L1 interaction presented in this work can provide guidance for the design of peptide and small molecule drugs targeting PD-1 or PD-L1.