Molecular Modelling and Dynamics Study of nsSNP in STXBP1 Gene in Early Infantile Epileptic Encephalopathy Disease
Molecular Modelling and Dynamics Study of nsSNP in STXBP1 Gene in Early Infantile Epileptic Encephalopathy Disease
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DOI：
10.1155/2019/4872101
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发表时间：
2019-12-31
影响因子：
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通讯作者：
Halima, Nahili
中科院分区：
文献类型：
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作者：
Al Mehdi, Krami;Benhnini, Fouad;Halima, Nahili
早期婴儿癫痫性脑病（称为大田原综合征）是最严重和最早的癫痫形式之一，其特征是早期癫痫发作。它影响新生儿和2至6岁的儿童。在与早期婴儿癫痫性脑病相关的基因中，编码参与SNARE复合物形成的Syntaxin结合蛋白1a的STXBP1基因有助于突触囊泡胞吐作用。本研究的目的是鉴定STXBP 1基因最致病的多态性，并确定它们对Stxbp 1蛋白结构和稳定性的影响。使用13种生物信息学工具预测STXBP1基因的高危非同义单核苷酸多态性（nsSNPs）。保守性分析由CONSURF Web服务器实现。利用YASARA软件分析致病性SNPs对Stxbp1蛋白结构的影响，并利用GROMACS软件进行分子动力学模拟。在245个nsSNP中，我们使用计算机预测工具鉴定出11个（S42P、H103D、R190W、R235G、D238E、L256P、P335S、C354Y、L365V、R406C和G544D）是有害的。保守性分析结果表明，这些nsSNPs均位于保守区域。对野生型Stxbp1结构及其突变体中的氢和疏水相互作用的比较表明，所有这些nsSNPs都在不同水平上影响蛋白质结构。分子动力学模拟结果表明，nsSNPs的总量在不同水平上影响蛋白质的稳定性、残差波动和压缩。这项研究为可能影响Stxbp1蛋白结构和功能的高风险nsSNPs提供了有用的信息。因此，在对患有早期婴儿癫痫性脑病的患者进行遗传筛查时，应考虑这些变异。
Early Infantile Epileptic Encephalopathy (known as Ohtahara Syndrome) is one of the most severe and earliest forms of epilepsy, characterized by early seizures onset. It affects newborns and children between two and six years old. Among the genes that have been associated with early infantile epileptic encephalopathy, the STXBP1 gene, which encodes the Syntaxin binding protein1a that is involved in SNARE complex formation, contributes to synaptic vesicles exocytosis. The aim of this study was to identify the most pathogenic polymorphisms of STXBP1 gene and determine their impact on the structure and stability of Stxbp1 protein. The high-risk nonsynonymous single nucleotide polymorphisms (nsSNPs) in the STXBP1 gene were predicted using 13 bioinformatics tools. The conservation analysis was realized by CONSURF web server. The analysis of the impact of the pathogenic SNPs on the structure of Stxbp1 protein was realized using YASARA software, and the molecular dynamics simulation was performed using GROMACS software. Out of 245 nsSNPs, we identified 11 (S42P, H103D R190W, R235G, D238E, L256P, P335S, C354Y, L365V, R406C, and G544D) as deleterious using in silico prediction tools. Conservation analysis results revealed that all these nsSNPs were located in conserved regions. The comparison of the hydrogen and hydrophobic interactions in the wild type Stxbp1 structure and its mutant forms showed that all these nsSNPs affect the protein structure on different levels. The molecular dynamics simulations revealed that the total of nsSNPs affect the protein stability, residual fluctuation, and the compaction at different levels. This study provides helpful information on high risk nsSNPs that may affect the Stxbp1 protein structure and function. Thus, these variants should be taken into consideration during the genetic screening of patients suffering from early infantile epileptic encephalopathy.