Functional and structural analysis of missense variants in the human PDCD1 Gene

Abstract

Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that regulates T-cell function by modulating and terminating immune responses.

Aim: This study investigates the functional and structural impact of missense single nucleotide polymorphisms in the human Programmed Cell Death 1 (PDCD1) gene.

Setting: The data related to PDCD1 gene single nucleotide polymorphisms [SNPs] were collected from dbSNP.

Methods: PredictSNP1.0, integrating eight tools (sorting intolerant from tolerant [SIFT], PolyPhen-1/2, multivariate analysis of protein polymorphism [MAPP], predictor of human deleterious [PhD] SNP, screening for non-acceptable polymorphisms [SNAP], PANTHER, nsSNPAnalyzer), was used for variant predictions. Conservation was assessed with ConSurf, stability with MUPro and I-Mutant 2.0 and pathogenicity with MutPred2. Molecular dynamics (MD) simulations analysed native and mutant PD-1 variants over 100 nanosecond (ns), assessing root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), radius of gyration (R_g), solvent-accessible surface area (SASA) and hydrogen bonding.

Results: D117V and W286G were identified as the most deleterious variants. However, W286G was located in an unfavourable structural region, rendering its model unreliable and excluding it from further analysis. Molecular dynamic simulations on the native and D117V models showed no significant differences in RMSD, RMSF, R_g, SASA or hydrogen bonding, suggesting D117V (rs772130993) has minimal impact on PD-1 stability or flexibility.

Conclusion: Bioinformatics tools predicted the D117V variant as deleterious, but molecular dynamics simulations suggest it may have limited functional impact.

Contribution: These findings underscore the importance of integrating computational predictions with experimental validation to guide therapeutic exploration of genetic variants.