Back to Search
Start Over
Computational Exploration of the Effects of Mutations on GABA Aminotransferase in GABA Aminotransferase Deficiency
- Source :
- International Journal of Molecular Sciences; Volume 24; Issue 13; Pages: 10933
- Publication Year :
- 2023
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2023.
-
Abstract
- Gamma-aminobutyric acid (GABA) transaminase—also called GABA aminotransferase (GABA-AT)—deficiency is a rare autosomal recessive disorder characterized by a severe neonatal-infantile epileptic encephalopathy with symptoms such as seizures, hypotonia, hyperreflexia, developmental delay, and growth acceleration. GABA transaminase deficiency is caused by mutations in GABA-AT, the enzyme responsible for the catabolism of GABA. Mutations in multiple locations on GABA-AT have been reported and their locations have been shown to influence the onset of the disease and the severity of symptoms. We examined how GABA-AT mutations influence the structural stability of the enzyme and GABA-binding affinity using computational methodologies such as molecular dynamics simulation and binding free energy calculation to understand the underlying mechanism through which GABA-AT mutations cause GABA-AT deficiency. GABA-AT 3D model depiction was carried out together with seven individual mutated models of GABA-AT. The structural stability of all the predicted models was analyzed using several tools and web servers. All models were evaluated based on their phytochemical values. Additionally, 100 ns MD simulation was carried out and the mutated models were evaluated using RMSD, RMSF, Rg, and SASA. gmxMMPBSA free energy calculation was carried out. Moreover, RMSD and free energy calculations were also compared with those obtained using online web servers. Our study demonstrates that P152S, Q296H, and R92Q play a more critical role in the structural instability of GABA-AT compared with the other mutated models: G465R, L211F, L478P, and R220K.
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences; Volume 24; Issue 13; Pages: 10933
- Accession number :
- edsair.multidiscipl..ce81e3f276f7eaae0c247c68105d4613
- Full Text :
- https://doi.org/10.3390/ijms241310933