1. Shedding light on cancer immunology at the molecular level: A quantum biochemistry study of representative PD-1/PD-L1 conformations.
- Author
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França VLB, Amaral JL, do Ó Pessoa C, Carvalho HF, and Freire VN
- Abstract
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
human PD-1human PD-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: ARG113L -ARG125L > ILE54L -VAL76L > ALA18L -ASP26L ; 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 ARG113L -ARG125L 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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