氟虫腈与斑马鱼GABAA及果蝇RDL受体作用的差异性研究

Differences of interactions between fipronil with zebrafish GABA_A and Drosophila melanogaster RDL receptor

采用同源建模的方法构建了斑马鱼γ-氨基丁酸A型（GABAA）受体和果蝇RDL（resistance to dieldrin）受体跨膜区的三维结构，研究了氟虫腈在两个受体中作用位点的差异；采用分子对接和分子动力学方法，探讨了氟虫腈与斑马鱼GABAA受体和果蝇RDL受体的结合模式，并比较了氟虫腈与两个受体作用的差异性。结果表明：斑马鱼 GABAA受体和氟虫腈作用位点的结构与果蝇RDL受体和氟虫腈作用位点的结构存在一定的差异，果蝇 RDL 受体中的 Ala301对应斑马鱼GABAA受体α1亚基中的Val284和γ2亚基中的Ser306，氨基酸构象的差异较大；氟虫腈与斑马鱼GABAA受体的结合位点靠近胞内区一端，而与果蝇RDL受体的结合位点则位于受体第二跨膜区的Ala301～Leu308区域内。复合物分子动力学模拟结果表明，在模拟过程中，两个受体与氟虫腈复合物体系的势能可很快达到平衡状态。斑马鱼GABAA受体与氟虫腈之间形成4个氢键，其中概率大于60％的氢键有2个；而尽管果蝇RDL受体与氟虫腈形成了6个氢键，但只有1个氢键的概率大于50％，其复合物结合的稳定性比前者低。

The three-dimensional models of the transmembrane domain of zebrafish （ Danio rerio ） GABAA receptor and fruitfly （ Drosophila melanogaster） RDL receptor were constructed by homology modeling based on the pore structure of nicotinic acetylcholine receptor, and the differences of fipronil binding sites in the two receptors were discussed. Molecular docking and molecular dynamics were used to investigate the different interactions between fipronil and the two receptors. The results indicated that the sequence identity was high, but the structure of fioronil binding sites in the two receptors were different. In zebrafish GABAA receptor, fipronil located at the bottom of the transmembrane domain, while in fruitfly RDL receptor, fipronil located within the region from Ala301 to Leu308. The two receptor-fipronil complexes were stable after molecular dynamics simulation. There were 4 hydrogen bonds generated between fipronil and zebrafish GABAA receptor, two of them whose frequency were higher than 60%. While, there were 6 hydrogen bonds in fruitfly RDL receptor-fipronil complex, but only one hydrogen bond with frequency higher than 50%. It was clear that the stability of fruitfly RDL receptor-fipronil complex was lower than that of zebrafish GABAA receptor-fipronil complex.