Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: a molecular modeling and dynamics approach
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.
KeywordsNF1 RAS-GAP domain K1444N (K1423N) Homology modeling Molecular dynamics simulation Variant classification
I would like to thank VIT management for providing the facility, seed money, and platform to carry out the research. No conflict of interest exists.
- Agrahari AK, Kumar A, Siva R et al (2018) Substitution impact of highly conserved arginine residue at position 75 in GJB1 gene in association with X-linked Charcot–Marie-tooth disease: a computational study. J Theor Biol 437:305–317. https://doi.org/10.1016/j.jtbi.2017.10.028 CrossRefPubMedGoogle Scholar
- Ali SK, Sneha P, Priyadharshini Christy J et al (2017) Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen gamma chain protein with the D356V mutation. J Biomol Struct Dyn 35:2714–2724. https://doi.org/10.1080/07391102.2016.1229634 CrossRefPubMedGoogle Scholar
- Andersen LB, Ballester R, Marchuk DA et al (1993) A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity. Mol Cell Biol 13:487–495. https://doi.org/10.1128/MCB.13.1.487.Updated CrossRefPubMedPubMedCentralGoogle Scholar
- Capriotti E, Calabrese R, Casadio R (2006) Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics 22:2729–2734. https://doi.org/10.1093/bioinformatics/btl423 CrossRefPubMedGoogle Scholar
- Doss CGP, Chakraborty C, Chen L, Zhu H (2014) Integrating in silico prediction methods, molecular docking, and molecular dynamics simulation to predict the impact of ALK missense mutations in structural perspective. Biomed Res Int 2014:895831–895814. https://doi.org/10.1155/2014/895831 CrossRefPubMedGoogle Scholar
- Doss CGP, Alasmar DR, Bux RI et al (2016) Genetic epidemiology of Glucose-6-dehydrogenase deficiency in the Arab world. Sci Rep 6. https://doi.org/10.1038/srep37284
- Hubbard RE, Kamran Haider M (2010) Hydrogen bonds in proteins: role and strength. In: Encyclopedia of life sciences. John Wiley & Sons, Ltd, ChichesterGoogle Scholar
- Krawczak M, Ball EV, Fenton I et al (2000) Human gene mutation database-a biomedical information and research resource. Hum Mutat 15:45–51. https://doi.org/10.1002/(SICI)1098-1004(200001)15:1<45::AID-HUMU10>3.0.CO;2-T CrossRefPubMedGoogle Scholar
- Poullet P, Lin B, Esson K, Tamanoi F (1994) Functional significance of lysine 1423 of neurofibromin and characterization of a second site suppressor which rescues mutations at this residue and suppresses RAS2Val-19-activated phenotypes. Mol Cell Biol 14:815–821. https://doi.org/10.1128/MCB.14.1.815 CrossRefPubMedPubMedCentralGoogle Scholar
- Sanjeev A, Mattaparthi VSK (2017) Computational investigation on the effects of H50Q and G51D mutations on the α-Synuclein aggregation propensity. J Biomol Struct Dyn 10:1–13Google Scholar
- Sneha P, George Priya Doss C (2016) Chapter seven – Molecular dynamics: New frontier in personalized medicine. In: Advances in protein chemistry and structural biology. 102:181–224Google Scholar
- Welti S, D’Angelo I, Scheffzek K (2008) Structure and function of neurofibromin. In: Neurofibromatoses. KARGER, Basel, 16:113–128Google Scholar