Computational analysis of structural and functional evaluation of the deleterious missense variants in the human...

CTLA-4 is an immune checkpoint receptor that negatively regulates the T-cell function expressed after T-cell activation to break the immune response. The current study predicted the genomic analysis to explore the functional variations of missense SNPs in the human CTLA4 gene using PolyPhen2, SIFT, PANTHER, PROVEAN, Fathmm, Mutation Assessor, PhD-SNP, SNPs&GO, SNAP2, and MutPred2. Phylogenetic conservation protein was predicted by ConSurf. Protein structural analysis was carried out by I-Mutant3, MUpro, iStable2, PremPS, and ERIS servers. Molecular dynamics trajectory analysis (RMSD, RMSF, Rg, SASA, H-bonds, and PCA) was performed to analyze the dynamic behavior of native and mutant CTLA-4 at the atomic level. Our in-silico analysis suggested that C58S, G118R, P137Q, P137R, P137L, P138T, and G146L variants were predicted to be the most deleterious missense variants and highly conserved residues. Moreover, the molecular dynamics analysis proposed a decrease in the protein stability and compactness with the P137R and P138T highlighting the impact of these variants on the function of the CTLA-4 protein.Communicated by Ramaswamy H. Sarma.