Molecular Dynamics Simulation of T10609C and C10676G Mutations of Mitochondrial ND4L Gene Associated With Proton Translocation in Type 2 Diabetes Mellitus and Cataract Patients

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 muta...

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Bibliographic Details
Published in:Bioinformatics and biology insights 2020, Vol.14, p.1177932220978672
Main Authors: Destiarani, Wanda, Mulyani, Rahmaniar, Yusuf, Muhammad, Maksum, Iman Permana
Format: Article
Language:English
Subjects:
Amino acids
Biomarkers
Cataracts
Computer applications
Deoxyribonucleic acid
Diabetes
Diabetes mellitus
Diabetes mellitus (non-insulin dependent)
DNA
Electron transport chain
Gene mapping
Hydrogen bonds
Mitochondrial DNA
Molecular dynamics
Mutants
Mutation
Mutation rates
ND4L gene
Original Research
Proteins
Protons
Translocation
Water chemistry
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Summary: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 ND4L 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.
ISSN:1177-9322
1177-9322
DOI:10.1177/1177932220978672