PMID- 29804243
OWN - NLM
STAT- MEDLINE
DCOM- 20190507
LR  - 20190507
IS  - 1573-7365 (Electronic)
IS  - 0885-7490 (Linking)
VI  - 33
IP  - 5
DP  - 2018 Oct
TI  - Computational insights of K1444N substitution in GAP-related domain of NF1 gene 
      associated with neurofibromatosis type 1 disease: a molecular modeling and 
      dynamics approach.
PG  - 1443-1457
LID - 10.1007/s11011-018-0251-1 [doi]
AB  - 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.
FAU - Agrahari, Ashish Kumar
AU  - Agrahari AK
AD  - Department of Integrative Biology, School of Biosciences and Technology, Vellore 
      Institute of Technology, Vellore, Tamil Nadu, 632014, India.
FAU - Muskan, Meghana
AU  - Muskan M
AD  - Department of Integrative Biology, School of Biosciences and Technology, Vellore 
      Institute of Technology, Vellore, Tamil Nadu, 632014, India.
FAU - George Priya Doss, C
AU  - George Priya Doss C
AD  - Department of Integrative Biology, School of Biosciences and Technology, Vellore 
      Institute of Technology, Vellore, Tamil Nadu, 632014, India. 
      georgecp77@yahoo.co.in.
FAU - Siva, R
AU  - Siva R
AD  - Department of Integrative Biology, School of Biosciences and Technology, Vellore 
      Institute of Technology, Vellore, Tamil Nadu, 632014, India.
FAU - Zayed, Hatem
AU  - Zayed H
AUID- ORCID: 0000-0001-8838-6638
AD  - Department of Biomedical Sciences, College of Health and Sciences, Qatar 
      University, Doha, Qatar. hatem.zayed@qu.edu.qa.
LA  - eng
PT  - Journal Article
DEP - 20180527
PL  - United States
TA  - Metab Brain Dis
JT  - Metabolic brain disease
JID - 8610370
RN  - 0 (Neurofibromin 1)
SB  - IM
MH  - Amino Acid Sequence
MH  - *Genes, Neurofibromatosis 1
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - *Mutation
MH  - Neurofibromatosis 1/*genetics
MH  - Neurofibromin 1/*genetics
MH  - Protein Conformation
OTO - NOTNLM
OT  - Homology modeling
OT  - K1444N (K1423N)
OT  - Molecular dynamics simulation
OT  - NF1
OT  - RAS-GAP domain
OT  - Variant classification
EDAT- 2018/05/29 06:00
MHDA- 2019/05/08 06:00
CRDT- 2018/05/28 06:00
PHST- 2017/11/12 00:00 [received]
PHST- 2018/05/17 00:00 [accepted]
PHST- 2018/05/29 06:00 [pubmed]
PHST- 2019/05/08 06:00 [medline]
PHST- 2018/05/28 06:00 [entrez]
AID - 10.1007/s11011-018-0251-1 [pii]
AID - 10.1007/s11011-018-0251-1 [doi]
PST - ppublish
SO  - Metab Brain Dis. 2018 Oct;33(5):1443-1457. doi: 10.1007/s11011-018-0251-1. Epub 
      2018 May 27.