Shedding light on cancer immunology at the molecular level: A quantum biochemistry study of representative PD-1/PD-L1 conformations

Background: Programmed death 1 (PD-1) binding to PD-L1 is a potent mechanism used by immunogenic tumors to evade the immune system and the immune checkpoint PD-1PD-L1 has emerged as a promising target in the search for new drugs to improve cancer treatment. The crystallographic structure of _humanPD-1_humanPD-L1 shed light on the molecular characterization of this system and allowed computational studies to be carried out to characterize structural behaviors.

Methods: This study demonstrated the importance of analyzing the flexibility of protein systems through molecular dynamics simulations (MDS) and its impacts on the interaction energy obtained through quantum biochemistry.

Results: The computational results obtained provide a description of the flexibility and energetic profile of the PD-1PD-L1 contact surface using representative conformations from MDS. Variations of up to 50 % in the total interaction energy values were detected depending on the scrutinized conformation, which can be mainly attributed to the flexibility of the CC' loop, FG loop and ASP85-GLN91 of PD-1 and the MET58-LYS62 segment of PD-L1. Quantum biochemistry revealed the three hot spots in PD-L1: ARG113_L-ARG125_L > ILE54_L-VAL76_L > ALA18_L-ASP26_L; and two energetic hot spots in PD-1: ALA125-ARG139 > VAL63-GLN88. Nonetheless, VAL63-GLN88 and GLY124-ARG139 exhibit significant variation in interaction energy between different conformations, while ARG113_L-ARG125_L is the only hot spot with high energetic fluctuation on the PD-L1 surface.

Conclusion: This is the first application of MDS coupled to dimensionality reduction and density functional theory (DFT) demonstrating new structural and energetic features that might be useful in discovering/designing more potent PD-1PD-L1 inhibitors.