Molecular dynamics simulations to decipher the structural and functional consequences of pathogenic missense mutations in the galactosylceramidase (GALC) protein causing Krabbe’s disease
| العنوان: | Molecular dynamics simulations to decipher the structural and functional consequences of pathogenic missense mutations in the galactosylceramidase (GALC) protein causing Krabbe’s disease |
|---|---|
| المؤلفون: | Nikita Jain, S. Udhaya Kumar, Prangya Paramita Jena, Siva Ramamoorthy, Hatem Zayed, C. George Priya Doss, D Thirumal Kumar |
| المصدر: | Journal of Biomolecular Structure and Dynamics. 39:1795-1810 |
| بيانات النشر: | Informa UK Limited, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Mutant, Mutation, Missense, Lysosomal storage disorder (LSD), Molecular dynamics, Molecular Dynamics Simulation, Biology, medicine.disease_cause, Structural Biology, Galactosylceramidase, medicine, Humans, Missense mutation, Molecular Biology, Genetics, Mutation, Galactocerebrosidase, Leukodystrophy, GALC, General Medicine, medicine.disease, Leukodystrophy, Globoid Cell, Molecular Docking Simulation, Krabbe disease, Molecular docking, DSSP (hydrogen bond estimation algorithm) |
| الوصف: | Krabbe disease (KD), also known as globoid cell leukodystrophy disease, is an autosomal recessive lysosomal storage genetic disorder, which is caused by the deficiency of galactocerebrosidase (GALC) coding gene (GALC). This study aimed to use extensive computational pipelines in understanding the missense mutations in GALC. We retrieved 176 mutations from the public databases and subjected them to pathogenicity, stability, and conservation analyses. The PredictSNP, iStable, and ConSurf prediction tools predicted 45, 95, and 47 mutations to be deleterious, destabilizing, and highly conserved, respectively. The R396L and R396W were the most deleterious and destabilizing to GALC, and were therefore prioritized for further analysis. Systematic validation on the impact of the R396L and R396W mutations to the chaperone alpha lobeline was performed using the molecular docking approach. The docking analysis revealed that the mutant R396W interacted with minimal binding affinity compared with both the R396L mutant and native GALC. Furthermore, the repetitive molecular dynamics simulation analysis showed that the mutant R396W demonstrated less compactness and reduced number of intramolecular hydrogen bonds compared with the mutant R396L and the native GALC. Overall, we observed higher structural and functional modifications in R396W positioned in the substrate-binding site. This was highly supported by the MMPBSA and DSSP analysis of the GROMACS. DSSP showed the transformation of turns to bends, indicating a loss of stability due to the R396W mutation. This study is expected to serve as a platform for prioritizing mutant proteins that could be a platform for both drug and target therapeuticsCommunicated by Ramaswamy H. Sarma. |
| تدمد: | 1538-0254 0739-1102 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de45ae04c6ec54d5d8b7f7e9728db1d3 https://doi.org/10.1080/07391102.2020.1742790 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....de45ae04c6ec54d5d8b7f7e9728db1d3 |
| قاعدة البيانات: | OpenAIRE |
PDF full text from Publisher | تدمد: | 15380254 07391102 |
|---|