Molecular insights into TGF-B signalling pathway disruption by non-synonymous SNPs variants in COPD: an in silico and...

Transforming Growth Factor Beta (TGF-B) signalling plays a central role in maintaining vascular homeostasis, regulating extracellular matrix production, and controlling pulmonary vascular remodelling. Disruption of this pathway has been closely associated with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD). Genetic variations, particularly non-synonymous single-nucleotide polymorphisms (nsSNPs), in key genes of the TGF-B cascade can lead to structural or functional alterations in the encoded proteins, thereby affecting pathway regulation and disease outcomes. In this study, nsSNPs in TGFB1, TGFBR1, TGFBR2, SMAD2, SMAD3, and SMAD4 were analysed using multiple computational tools including SIFT, PolyPhen2, PANTHER, PhD-SNP, MetaSNP, PredictSNP2, SNAP2, CADD, REVEL, and MutPred2 to predict deleterious variants. ConSurf was used to evaluate evolutionary conservation, and ProtParam assessed physicochemical changes between wild-type and mutant proteins. Protein structural models for wild-type and mutant variants were generated using I-TASSER and validated through Ramachandran plots. Furthermore, protein-protein docking and molecular dynamics (MD) simulations were conducted to investigate the structural stability and binding effects between TGF-B and its receptor, TGFBRII. A total of 42 high-confidence deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) were identified across the six genes, with specific variants, such as R156C of TGFB and N384S of TGFBRII, showing major destabilising effects on receptor conformation, and E313D of TGFB inducing structural compaction that may impair signal transduction. Overall, these computational findings suggest that deleterious nsSNPs in the TGF-B signalling components may alter protein stability and disrupt pathway communication, potentially influencing PH-associated COPD pathogenesis and offering future avenues for therapeutic targeting.