Computational analysis and molecular dynamics simulation of high-risk single nucleotide polymorphisms of the <i>ADAM10</i> gene

Polymorphisms of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) are linked to pathophysiological changes in lung inflammation, cancer, Alzheimer’s disease (AD), encephalopathy, liver fibrosis, and cardiovascular diseases. In this study, we predicted the pathogenicity of <i>ADAM10</i> non-synonymous single nucleotide polymorphisms (nsSNPs) in a wide array of mutation analyzing bioinformatics tools. We retrieved 423 nsSNPs from dbSNP-NCBI for the analysis, and 13 were predicted deleterious by each of the ten tools: SIFT, PROVEAN, CONDEL, PANTHER-PSEP, SNAP2, SuSPect, PolyPhen-2, Meta-SNP, Mutation Assessor and Predict-SNP. Further assessment of amino acid sequences, homology models, conservation profiles, and inter-atomic interactions identified C222G, G361E and C639Y as the most pathogenic mutations. We validated this prediction through structural stability analysis using DUET, I-Mutant Suite, SNPeffect and Dynamut. Molecular dynamics simulations and principal component analysis also indicated considerable instability of the C222G, G361E and C639Y variants. Therefore, these <i>ADAM10</i> nsSNPs could be candidates for diagnostic genetic screening and therapeutic molecular targeting. Communicated by Ramaswamy H. Sarma