Abstract：
The 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) at position 174 is conserved across many species, proposedly holding important characteristics for the functions of FGF5. 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-H174). It was found that the mutation decreased number of hydrogen bonds within the protein, sheet secondary structure, interaction of residue 174 with other residues, and number of salt-bridges. On the other hand, the mutation increased 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 of the FGFR1-FGF5-H174 complex was drastically different from that of the FGFR1-FGF5-WT complex. In conclusion, the missense mutation conferred more instability within itself and stronger binding affinity towards FGFR1 with distinctively altered binding mode or residue connectivity. These findings might help explain the decreased pharmacological activity of FGF5-H174 towards FGFR1, underlying trichomegaly.Communicated by Ramaswamy H. Sarma.
摘要：
FGF5的错义突变Y174H（FGF5-H174）与毛眼肥大有关，以异常长且有色素的睫毛为特征。174位的氨基酸酪氨酸（Tyr/Y）在许多物种中都是保守的，提出了FGF5功能的重要特征。采用微秒分子动力学模拟以及蛋白质-蛋白质对接和残基相互作用网络分析来研究野生型（FGF5-WT）及其突变对应物（FGF5-H174）的结构动力学和结合模式。发现突变减少了蛋白质内的氢键数量，板材二级结构,残基174与其他残基的相互作用，和盐桥的数量。另一方面,突变增加了溶剂可及的表面积，蛋白质和溶剂之间的氢键数，线圈次级结构，蛋白C-α骨架均方根偏差，蛋白质残基均方根波动，以及占用的构象空间。此外,结合分子动力学模拟和分子力学的蛋白质-蛋白质对接-泊松-玻尔兹曼表面积（MM/PBSA）结合能计算表明，突变的变体对成纤维细胞生长因子受体1（FGFR1）具有更强的结合亲和力。然而,残基相互作用网络分析表明，FGFR1-FGF5-H174复合物的结合模式与FGFR1-FGF5-WT复合物的结合模式截然不同。总之,错义突变赋予自身更多的不稳定性和对FGFR1更强的结合亲和力,具有明显改变的结合模式或残基连接.这些发现可能有助于解释FGF5-H174对FGFR1的药理活性降低，这是毛眼肥大的基础。由RamaswamyH.Sarma沟通。
