title: Screening of mutations affecting protein stability and dynamics of FGFR1-A simulation analysis.
abstract: Single amino acid substitutions in Fibroblast Growth Factor Receptor 1 (FGFR1) destabilize protein and have been implicated in several genetic disorders like various forms of cancer, Kallamann syndrome, Pfeiffer syndrome, Jackson Weiss syndrome, etc. In order to gain functional insight into mutation caused by amino acid substitution to protein function and expression, special emphasis was laid on molecular dynamics simulation techniques in combination with in silico tools such as SIFT, PolyPhen 2.0, I-Mutant 3.0 and SNAP. It has been estimated that 68% nsSNPs were predicted to be deleterious by I-Mutant, slightly higher than SIFT (37%), PolyPhen 2.0 (61%) and SNAP (58%). From the observed results, P722S mutation was found to be most deleterious by comparing results of all in silico tools. By molecular dynamics approach, we have shown that P722S mutation leads to increase in flexibility, and deviated more from the native structure which was supported by the decrease in the number of hydrogen bonds. In addition, biophysical analysis revealed a clear insight of stability loss due to P722S mutation in FGFR1 protein. Majority of mutations predicted by these in silico tools were in good concordance with the experimental results.
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: C George Priya
authors.initials: CG
authors.lastname: Doss
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: B
authors.initials: B
authors.lastname: Rajith
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Nimisha
authors.initials: N
authors.lastname: Garwasis
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Pretty Raju
authors.initials: PR
authors.lastname: Mathew
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Anand Solomon
authors.initials: AS
authors.lastname: Raju
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: K
authors.initials: K
authors.lastname: Apoorva
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Denise
authors.initials: D
authors.lastname: William
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: N R
authors.initials: NR
authors.lastname: Sadhana
authors.affiliation: Centre for Nanobiotechnology, Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Tanwar
authors.initials: T
authors.lastname: Himani
authors.affiliation: Department of Biological Sciences, Covenant University, Nigeria.
authors.forename: I P
authors.initials: IP
authors.lastname: Dike
keywords: FGFR1; FGFR1, Fibroblast growth factor type 1; GD, Grantham Deviation; GV, Grantham Variance; MSA, Multiple Sequence Alignments; Molecular dynamics simulation; NCBI, National Center for Biological Information; OMIM, Online Mendelian Inheritance in Man; PolyPhen 2.0, Polymorphism Phenotyping; RI, Reliability Index; RMSD, Root Mean Square Deviation; RMSF, Root Mean Square Fluctuation; SIFT, Sorting Intolerant From Tolerant; SNAP, Screening for Non acceptable Polymorphisms; SNPs; SNPs, Single Nucleotide Polymorphisms; SPC, Simple Point Charge