立体异构和羧基甲酯化对PDZ结构域抑制剂与nNOS PDZ相互作用的影响

The Effect of Stereoisomerism and Carboxyl Methyl-esterification on the Interaction between PDZ Domain Inhibitors and nNOS PDZ Domain

ZLc-002及其类似物是一系列PDZ结构域抑制剂,它们能够不同程度地阻断nNOS与CAPON之间的偶联,从而表现了不同的抗焦虑活性(PDZ指最早发现含有此结构域的三个蛋白质的首字母缩写,分别是:post synaptic density protein-95,PSD-95;drosophila disc large tumor suppressor gene,DLG;zonula occludens-1 protein,ZO-1。即:突触后密度蛋白95,果蝇光盘大肿瘤抑制剂,和闭锁小带蛋白1。nNOS:neuronal nitric oxide synthase,即神经元型一氧化氮合酶。CAPON:carboxy-terminal PDZ ligand,即神经型一氧化氮合酶羧基末端PDZ结合配体)。为了探究立体异构和羧基甲酯化对PDZ结构域抑制剂与nNOS PDZ之间相互作用的影响,分别应用分子对接、分子动力学模拟,以及传统的和可极化的分子力场,对比研究了3个PDZ结构域抑制剂与nNOS PDZ之间的相互作用方式和强度。研究发现,羧基甲酯化的R型构象的PDZ结构域抑制剂与nNOS PDZ结构域相互作用最强,这与实验上测得的CAPON-nNOS解偶联率相一致。还计算和分析了抑制剂与nNOS PDZ相互作用能的不同分项,结果表明:立体异构和羧基酯化对PDZ结构域抑制剂与nNOS PDZ间的氢键相互作用具有重要影响,而对二者之间的范德华相互作用影响较小。

ZLc-002 and its analogues are PDZ domain inhibitors,which can break the interactions between nNOS and CAPON and have anti-anxiety activities（ PDZ is an acronym combining the first letters of three protein（ post synaptic density protein-95,PSD-95; drosophila disc large tumor suppressor gene,DLG; zonula occludens-1protein,ZO-1. nNOS： neuronal nitric oxide synthase. CAPON： carboxy-terminal PDZ ligand）. To understand the effect of stereoisomerism and carboxyl methyl-esterification on the interaction between PDZ domain inhibitors and nNOS PDZ domain,molecular docking,molecular dynamics simulation,traditional and polarizable force fields have been employed to investigate the interaction mode and strength between three PDZ domain inhibitors and nNOS PDZ. It is found that R-PDZ domain inhibitor,which has carboxyl methyl-esterification,has the strongest interaction with the nNOS PDZ domain,which is in good agreement with the experimental CAPON-nNOS uncoupling ratio. In addition,different terms of interaction energies have been calculated,showing stereoisomerism and carboxyl methyl-esterification play a more important role in the intermolecular hydrogen-bonding interaction between PDZ domain inhibitors and nNOS PDZ domain than the Van der Waals interaction.