Molecular Dynamics Simulation of Kir6.2 Variants Reveals Potential Association with Diabetes Mellitus

Mohamed E Elangeeb; Imadeldin Elfaki; Ali M S Eleragi; Elsadig Mohamed Ahmed; Rashid Mir; Salem M Alzahrani; Ruqaiah I Bedaiwi; Zeyad M Alharbi; Mohammad Muzaffar Mir; Mohammad Rehan Ajmal; Faris Jamal Tayeb; Jameel Barnawi

doi:10.3390/molecules29081904

Molecular Dynamics Simulation of Kir6.2 Variants Reveals Potential Association with Diabetes Mellitus

Molecules. 2024 Apr 22;29(8):1904. doi: 10.3390/molecules29081904.

Affiliations

¹ Department of Basic Medical Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia.
² Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia.
³ Department of Microbiology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁴ Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 61922, Saudi Arabia.
⁵ Department of Clinical Chemistry, Faculty of Medical Laboratory Sciences, University of El Imam El Mahdi, Kosti 27711, Sudan.
⁶ Department of Medical Laboratory Technology, Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁷ Department of Clinical Biochemistry, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.

Abstract

Diabetes mellitus (DM) represents a problem for the healthcare system worldwide. DM has very serious complications such as blindness, kidney failure, and cardiovascular disease. In addition to the very bad socioeconomic impacts, it influences patients and their families and communities. The global costs of DM and its complications are huge and expected to rise by the year 2030. DM is caused by genetic and environmental risk factors. Genetic testing will aid in early diagnosis and identification of susceptible individuals or populations using ATP-sensitive potassium (K_ATP) channels present in different tissues such as the pancreas, myocardium, myocytes, and nervous tissues. The channels respond to different concentrations of blood sugar, stimulation by hormones, or ischemic conditions. In pancreatic cells, they regulate the secretion of insulin and glucagon. Mutations in the KCNJ11 gene that encodes the Kir6.2 protein (a major constituent of K_ATP channels) were reported to be associated with Type 2 DM, neonatal diabetes mellitus (NDM), and maturity-onset diabetes of the young (MODY). Kir6.2 harbors binding sites for ATP and phosphatidylinositol 4,5-diphosphate (PIP2). The ATP inhibits the K_ATP channel, while the (PIP2) activates it. A Kir6.2 mutation at tyrosine330 (Y330) was demonstrated to reduce ATP inhibition and predisposes to NDM. In this study, we examined the effect of mutations on the Kir6.2 structure using bioinformatics tools and molecular dynamic simulations (SIFT, PolyPhen, SNAP2, PANTHER, PhD&SNP, SNP&Go, I-Mutant, MuPro, MutPred, ConSurf, HOPE, and GROMACS). Our results indicated that M199R, R201H, R206H, and Y330H mutations influence Kir6.2 structure and function and therefore may cause DM. We conclude that MD simulations are useful techniques to predict the effects of mutations on protein structure. In addition, the M199R, R201H, R206H, and Y330H variant in the Kir6.2 protein may be associated with DM. These results require further verification in protein-protein interactions, Kir6.2 function, and case-control studies.

Keywords: ATP-sensitive potassium channels (KATP channels); KCNJ11 gene; bioinformatics; diabetes mellitus; genetic testing; nsSNPs.

MeSH terms

Binding Sites
Diabetes Mellitus* / genetics
Diabetes Mellitus* / metabolism
Genetic Predisposition to Disease
Humans
Molecular Dynamics Simulation*
Mutation
Potassium Channels, Inwardly Rectifying* / chemistry
Potassium Channels, Inwardly Rectifying* / genetics
Potassium Channels, Inwardly Rectifying* / metabolism
Protein Binding

Substances

Potassium Channels, Inwardly Rectifying
Kir6.2 channel

Grants and funding

This research receives no external funding.