ADAM10基因高风险单核苷酸多态性的计算分析和分子动力学模拟。
Computational analysis and molecular dynamics simulation of high-risk single nucleotide polymorphisms of the ADAM10 gene.
发表日期:2023 Mar 30
作者:
Jannatun Nayem Namme, Hasan Mahmud Reza, Asim Kumar Bepari
来源:
Alzheimers & Dementia
摘要:
ADAM10蛋白质的多态性与肺炎症、癌症、阿尔茨海默病(AD)、脑病、肝纤维化和心血管疾病的病理生理学变化有关。在这项研究中,我们使用多种突变分析生物信息学工具预测ADAM10非同义单核苷酸多态性(nsSNPs)的致病性。我们从dbSNP-NCBI中检索了423个nsSNPs进行分析,其中有13个被十个工具中的每一个都预测为有害:SIFT、PROVEAN、CONDEL、PANTHER-PSEP、SNAP2、SuSPect、PolyPhen-2、Meta-SNP、Mutation Assessor和Predict-SNP。进一步评估氨基酸序列、同源性模型、保守性剖面和原子间相互作用,确定C222G、G361E和C639Y为最具致病性的突变。我们通过使用DUET、I-Mutant Suite、SNPeffect和Dynamut进行结构稳定性分析来验证这种预测。分子动力学模拟和主成分分析也表明C222G、G361E和C639Y变异体具有相当大的不稳定性。因此,这些ADAM10 nsSNPs可能成为诊断遗传筛查和治疗分子靶向筛选的候选基因。由Ramaswamy H. Sarma传达。
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 ADAM10 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 ADAM10 nsSNPs could be candidates for diagnostic genetic screening and therapeutic molecular targeting.Communicated by Ramaswamy H. Sarma.