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01-10-2018 | Original Article

Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: a molecular modeling and dynamics approach

Authors: Ashish Kumar Agrahari, Meghana Muskan, C. George Priya Doss, R. Siva, Hatem Zayed

Published in: Metabolic Brain Disease | Issue 5/2018

Abstract

The NF1 gene encodes for neurofibromin protein, which is ubiquitously expressed, but most highly in the central nervous system. Non-synonymous SNPs (nsSNPs) in the NF1 gene were found to be associated with Neurofibromatosis Type 1 disease, which is characterized by the growth of tumors along nerves in the skin, brain, and other parts of the body. In this study, we used several in silico predictions tools to analyze 16 nsSNPs in the RAS-GAP domain of neurofibromin, the K1444N (K1423N) mutation was predicted as the most pathogenic. The comparative molecular dynamic simulation (MDS; 50 ns) between the wild type and the K1444N (K1423N) mutant suggested a significant change in the electrostatic potential. In addition, the RMSD, RMSF, Rg, hydrogen bonds, and PCA analysis confirmed the loss of flexibility and increase in compactness of the mutant protein. Further, SASA analysis revealed exchange between hydrophobic and hydrophilic residues from the core of the RAS-GAP domain to the surface of the mutant domain, consistent with the secondary structure analysis that showed significant alteration in the mutant protein conformation. Our data concludes that the K1444N (K1423N) mutant lead to increasing the rigidity and compactness of the protein. This study provides evidence of the benefits of the computational tools in predicting the pathogenicity of genetic mutations and suggests the application of MDS and different in silico prediction tools for variant assessment and classification in genetic clinics.

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Title: Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: a molecular modeling and dynamics approach
Authors: Ashish Kumar Agrahari
Meghana Muskan
C. George Priya Doss
R. Siva
Hatem Zayed
Publication date: 01-10-2018
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 5/2018
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-018-0251-1

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Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: a molecular modeling and dynamics approach

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