Destiarani Wanda, Mulyani Rahmaniar, Yusuf Muhammad, Maksum Iman Permana
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Sumedang, Indonesia.
Research Center for Molecular Biotechnology and Bioinformatics, Universitas Padjadjaran, Bandung, Indonesia.
Bioinform Biol Insights. 2020 Dec 16;14:1177932220978672. doi: 10.1177/1177932220978672. eCollection 2020.
The mutation rate of mitochondrial DNA (mtDNA) is 17 times higher than nuclear DNA, and these mutations can cause mitochondrial disease in 1 of 10.000 people. The T10609C mutation was identified in type 2 diabetes mellitus (T2DM) patients and the C10676G mutation in cataract patients, with both mutations occurring in the gene of mtDNA that encodes ND4L protein. ND4L protein, a subunit of complex I in the respiratory complex, has been shown to play a role in the proton translocation process. The purpose of this study was to investigate the effect of both mutations on the proton translocation mechanism. Mutation mapping showed changes in amino acids M47T (T10609C) and C69W (C10676G). The 100 ns molecular dynamics (MD) simulations performed on native and mutants of ND4L-ND6 subunits. It is revealed that the native model had a similar proton translocation pathway to that of complex I from other organisms. Interestingly, the mutant M47T and C69W showed the interruption of the translocation pathway by a hydrogen bond formation between Glu34 and Tyr157. It is observed that the mutations were restricting the passage of water molecules through the transmembrane region. These results could help to develop the computational assay for the validation of a specific genetic biomarker for T2DM and cataracts.
线粒体DNA（mtDNA）的突变率比核DNA高17倍，这些突变可导致万分之一的人患线粒体疾病。在2型糖尿病（T2DM）患者中发现了T10609C突变，在白内障患者中发现了C10676G突变，这两种突变都发生在mtDNA编码ND4L蛋白的基因中。ND4L蛋白是呼吸复合体中复合体I的一个亚基，已被证明在质子转运过程中起作用。本研究的目的是研究这两种突变对质子转运机制的影响。突变图谱显示氨基酸M47T（T10609C）和C69W（C10676G）发生了变化。对ND4L-ND6亚基的天然型和突变型进行了100纳秒的分子动力学（MD）模拟。结果表明，天然模型的质子转运途径与其他生物体的复合体I相似。有趣的是，突变体M47T和C69W显示，Glu34和Tyr157之间形成氢键，导致转运途径中断。据观察，这些突变限制了水分子通过跨膜区域。这些结果有助于开发用于验证T2DM和白内障特定遗传生物标志物的计算分析方法。
