Structural insights into the impacts of non-synonymous single nucleotide polymorphisms in CD274 gene on the PD-1/PD-L1 interaction: An in silico approach

Abstract

Programmed cell death ligand 1 (PD-L1) on tumor cells interacts with PD-1 of activated T cells causing immune evasion. Polymorphisms in CD274 gene encoding PD-L1 have been associated with several cancer types. In this study, various bioinformatics tools were employed to identify the most deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in CD274 gene that could alter the structure and function of PD-L1. A database search through cBioPortal, ClinVar, COSMIC, gnomAD and HGMD identified total 137 nsSNPS located at the IgV domain of PD-L1 responsible for receptor binding. These mutations were further screened by several insilico tools: PolyPhen2, PhD-SNP, FATHMM, Meta-SNP, PANTHER-PSEP, SIFT, MutPred2, mCSM, MUpro, I-mutant 2.0, INPS-MD, ConSurf, HOPE, and NetSurfP-3.0 for determining the impact of these mutations on the structure of PD-L1. Based on the consensus among various algorithms, 39 nsSNPs were identified to have deleterious effects, including altered protein stability. The binding affinity of mutated PD-L1 proteins with PD-1 was studied by molecular docking and dynamic simulations. Two highly conserved nsSNPs, C40R and V104L were found to enhance binding affinity to PD-1, with a greater impact on structure and function. These results underline the potential structural and functional consequences of these nsSNPs on PD-L1.

Keywords: CD274 polymorphisms; Immune checkpoint; PD-L1; nSNPs.