Computational exploration of genetic variants through structure modeling, protein-ligand docking, and molecular dynamics simulation.

The urea transporter UT-B1, encoded by the gene, has been hypothesized to be a significant protein whose deficiency and dysfunction contribute to the pathogenesis of bladder cancer and many other diseases. Several studies reported the association of genetic alterations in the (UT-B1) gene with bladder carcinogenesis, suggesting a need for thorough characterization of the UT-B1 protein's coding and non-coding variants. This study used various computational techniques to investigate the commonly occurring germ-line missense and non-coding SNPs (ncSNPs) of the gene (UT-B1) for their structural, functional, and molecular implications for disease susceptibility and dysfunctionality. missense variants, primarily identified from the ENSEMBL genome browser, were screened through twelve functionality prediction tools leading to two variants D280Y (predicted detrimental by maximum tools) and D280N (high global MAF) for rs1058396. Subsequently, the ConSurf and NetSurf tools revealed the D280 residue to be in a variable site and exposed on the protein surface. According to I-Mutant2.0 and MUpro, both variants are predicted to cause a significant effect on protein stability. Analysis of molecular docking anticipated these two variants to decrease the binding affinity of UT-B1 protein for the examined ligands to a significant extent. Molecular dynamics also disclosed the possible destabilization of the UT-B1 protein due to single nucleotide polymorphism compared to wild-type protein which may result in impaired protein function. Furthermore, several non-coding SNPs were estimated to affect transcription factor binding and regulation of gene expression. Additionally, two ncSNPs were found to affect miRNA-based post-transcriptional regulation by creating new seed regions for miRNA binding. This comprehensive study of gene variants may serve as a springboard for future large-scale investigations examining polymorphisms.