In silico Assessment of the Arg85Trp Glucokinase Mutation Effects

F. Bouldjennet, S. Bouaziz-Terrachet, M. Azzouz, R. Raache
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Abstract

Maturity Onset Diabetes of the Young (MODY) is a heterogeneous group of autosomal dominantly inherited, young-onset β-cell disorders that account for approximately 2% of non-insulin-dependent diabetics in Europe. MODY2 or GCK-MODY is caused by inactivating heterozygous mutations in the glucokinase. Linkage of MODY to the Arg85Trp GCK mutation, among Algerian diabetic patients has been established in our previous research. The main objective of this study is to strengthen the evidence for the pathogenicity of this mutation using bioinformatics tools. For this purpose, prediction of Arg85Trp mutation effect on glucokinase (PDB ID: 1V4T) stability was performed using I-Mutant 3.0, PoPMuSiC 3.1, DUET and mCSM web servers. Otherwise, structural analysis was performed after optimization of the native and the mutated structures (PDB ID: 1V4T). For that the steepest descent geometries optimization were applied using Nano Molecular Dynamics software (NAMD 2.12). Subsequently, interactions established between the native Arg85 or the mutated Trp85 and the surrounding residues were studied using Accelrys Discovery Studio Visualizer software. In silico analysis conducted through I-Mutant 3.0, PoPMuSiC 3.1, DUET and mCSM softwares, predicts the Arg85Trp as a destabilizing mutation. Structural modeling gives further evidence in favor of the pathogenicity of this mutation. Overall, our results corroborate with the previous metabolic and in silico studies which associate Arg85Trp mutation to MODY phenotype.
Arg85Trp葡萄糖激酶突变效应的计算机评价
成熟型糖尿病(MODY)是一种常染色体显性遗传的异质组,年轻型β细胞疾病约占欧洲非胰岛素依赖型糖尿病患者的2%。MODY2或GCK-MODY是由葡萄糖激酶杂合突变失活引起的。在阿尔及利亚糖尿病患者中,MODY与Arg85Trp GCK突变的连锁关系已经在我们之前的研究中建立。本研究的主要目的是利用生物信息学工具加强该突变致病性的证据。为此,利用I-Mutant 3.0、PoPMuSiC 3.1、DUET和mCSM web服务器预测Arg85Trp突变对葡萄糖激酶(PDB ID: 1V4T)稳定性的影响。否则,在对原生和突变结构(PDB ID: 1V4T)进行优化后进行结构分析。为此,采用纳米分子动力学软件(NAMD 2.12)对最陡下降几何形状进行优化。随后,使用Accelrys Discovery Studio Visualizer软件研究原生Arg85或突变Trp85与周围残基之间建立的相互作用。通过I-Mutant 3.0、PoPMuSiC 3.1、DUET和mCSM软件进行的硅分析预测Arg85Trp是一个不稳定突变。结构模型进一步证明了这种突变的致病性。总的来说,我们的结果与之前的代谢和计算机研究相吻合,这些研究将Arg85Trp突变与MODY表型联系起来。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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