Molecular Dynamics Simulation of T10609C and C10676G Mutations of MitochondrialND4LGene Associated With Proton Translocation in Type 2 Diabetes Mellitus and Cataract Patients

Abstract

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.

In Silico Study of Mangostin Compounds and Its Derivatives as Inhibitors of α-Glucosidase Enzymes for Anti-Diabetic Studies

“…Many studies on this disease, especially bioinformatics studies, have been conducted. T10609C and C10676G mutations in mitochondrial DNA can affect proton translocation, leading to MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), ataxia, CPEO (chronic progressive external ophthalmoplegia), LHON (Leber hereditary optic neuropathy), and MIDD (maternally inherited diabetes and deficiency) [ 32 ]. This mutation is often accompanied by mutations in A3243G and G9053A, which can alter the structure of the mitochondrial leucine tRNA and ATPase6 [ 33 , 34 ] and trigger an increase in cellular oxidative stress.…”

Computational simulations of microalgae-derived bioactive compounds as a novel inhibitor against B-Raf V600E-driven melanoma

“…Therefore, this study modeled the full length of the native B-Raf receptor and the V600E mutant using Modeller 10.1 to investigate further anticancer melanoma candidates through molecular docking, virtual screening, and molecular dynamics simulation. PROCHECK (Laskowski et al, 1993) and the DOPE profile comparison of the model and template (Webb and Sali, 2016) were used to evaluate the B-Raf V600E models (Destiarani et al, 2020). These methods were able to rule out the protein structure with imprecise stereochemical features such as steric hindrance, improper hydrogen bonds, and distorted bond angles.…”

“…Melanoma is the deadliest skin cancer that arises due to genetic mutations in cells that produce melanin, called melanocytes (Domingues et al, 2018). Melanoma represents less than 5% of all malignancies.…”

Molecular Dynamics Simulation of a tRNA-Leucine Dimer with an A3243G Heteroplasmy Mutation in Human Mitochondria Using a Secondary Structure Prediction Approach

“…Interestingly, A3243G was found in patients with pure cataracts, a non-neuromuscular disease, and could be a potential biomarker because of impaired ATP metabolism due to mutations in the respiratory complex. Another secondary mutation that also occurs in the genome carrying A3243G is T10609C, which was found in type-2 diabetes mellitus (T2DM) patients but has also been reported to be associated with Leber Hereditary Optic Neuropathy (LHON) disease in a Kuwait family, 11 and C10676G found in cataract patients [7].…”