Fibroblast Growth Factor 5 (FGF5) and Its Missense Mutant FGF5-H174 Underlying Trichomegaly: A Molecular Dynamics Simulation Investigation

Abstract

AbstractThe missense mutation Y174H of FGF5 (FGF5-H174) had been associated with trichomegaly, characterized by abnormally long and pigmented eyelashes. The amino acid tyrosine (Tyr/Y) is conserved across many species, proposedly holding important characteristics for the functions of FGF5. One-microsecond molecular dynamics simulations along with protein-protein docking and residue interacting network analysis were employed to investigate the structural dynamics and binding mode of both wild-type (FGF5-WT) and its mutated counterpart (FGF5-Y174H). It was found that the mutation caused decreases in number of hydrogen bonds within the protein, sheet secondary structure, interaction of residues 174 with others, and number of salt-bridges. On the other hand, the mutation showed increases in solvent accessible surface area, number of hydrogen bonds between the protein and solvent, coil secondary structure, protein C-alpha backbone root mean square deviation, protein residue root mean square fluctuations, as well as occupied conformational space. In addition, protein-protein docking integrated with molecular dynamics simulations and molecular mechanics - Poisson-Boltzmann surface area (MM/PBSA) binding energy calculation demonstrated that the mutated variant possessed stronger binding affinity towards fibroblast growth factor receptor 1 (FGFR1). However, residue interaction network analysis demonstrated that the binding mode was drastically different from that of the FGF5-WT-FGFR1 complex. In conclusion, the missense mutation conferred more instability, stronger binding affinity towards FGFR1 but with distinctively altered binding mode or residue connectivity. These findings might help explain the decreased activation of FGFR1, underlying trichomegaly.