芳香烃受体—配基互作模式的分子动力学模拟

发布时间：2018-05-23 21:34

本文选题：分子模拟 + 分子对接　；参考：《西南交通大学》2017年硕士论文

【摘要】：芳香烃受体(aryl hydrocarbon receptor,AhR)属于配体依赖性的碱性螺旋-环-螺旋(basic helix-loop-helix,bHLH)转录因子超家族中的 PAS(Per-Arnt-Sim)亚家族,可通过与一些环境污染物结合激活下游多种基因表达,进而介导致癌、致畸和生物转化等作用。AhR配体可以分为合成配体与天然配体两类,合成配体包括有毒的卤代芳香烃类(HAHs),多环芳香烃类(PAHs)及其衍生物,如多氯代二苯并-对-二恶英(PCDDs),二苯并呋喃(PCDFs),四氯二苯并-p-二恶英(TCDD)等;在非环境污染物作为配体时AhR则扮演不同的生理学角色,如影响细胞生长、分化和凋亡,调控自身免疫,炎症以及癌症进程。本文通过对野生型(WT)和三个突变模型(Phe289Ala,Tyr316Ala,Ile319Ala)利用GROMACS软件包中的amber99sb力场进行分子动力学模拟,从蛋白稳定性,蛋白结构变化,蛋白结合腔变化,及蛋白和配体结合能力4个方面分析三个残基的门控作用。通过对AhR LBD与不同配体形成的复合物结构进行分子动力学模拟,从蛋白与配体结合模式,配体结合能量变化,蛋白结构变化和结合腔变化4个方面分析不同配体对AhR LBD结构域产生的影响。研究发现Phe289、Tyr316、Ile319三个疏水性氨基酸残基的突变将会降低AhR配体结合结构域(AhRLBD)环境的稳定性,并且通过疏水联系扮演一个"门控"残基的作用。整体的结构分析表明结合腔附近的突变会降低结合腔的稳定性,导致明显的柔性变化并且导致配体活性降低和逃逸。把AhR与不同类型的配体进行模拟,发现不同的配体在AhR LBD结构域中有不同的结合位点。然而一些关键的氨基酸残基,如Phe289,Phe318,Gln377等。这些氨基酸残基位点对于不同的配体可能有不同的构象以更加契合小分子从而牢牢结合小分子配体。我们同样发现氨基酸残基Phe289,Ile319和Met342对于不同配体具有较高的能量贡献。同时AhR在宏观上可以调整自己的构象与形状从而适应不同结构的配体,主要的柔性运动发生在A-B-loop以及E-alpha上。本研究结果为深入认识配体对AhR蛋白的作用机制,以及以AhR蛋白为靶点的药物设计、筛选和产品开发提供了重要理论依据。
[Abstract]:Aryl hydrocarbon receptor AhR belongs to the basic helix-loop-helix-helixhlhh transcriptional factor superfamily of ligand-dependent alkaline helix-loop-helix-helixhlhh, which can activate downstream gene expression by binding with some environmental pollutants, and then mediate carcinogenesis. Teratogenicity and biotransformation. AhR ligands can be divided into synthetic ligands and natural ligands. The synthetic ligands include toxic halogenated aromatic hydrocarbons (HAHsN), polycyclic aromatic hydrocarbons (PAHs) and their derivatives. For example, PCDDs, dibenzofuran, tetrachlorodibenzo-pdioxin (TCDD) and AhR play different physiological roles when non-environmental pollutants are used as ligands, such as affecting cell growth, differentiation and apoptosis. Regulate autoimmune, inflammation and cancer progression. In this paper, by using the amber99sb force field in the GROMACS software package, the molecular dynamics simulation was carried out on the wild type of WTT and three mutant models, Phe289Ala-Tyr316AlaAla-Ile319Ala. from the aspects of protein stability, protein structure change and protein binding cavity change, the molecular dynamics simulation was carried out by using the amber99sb force field in the GROMACS software package. And four aspects of binding ability of protein and ligand were used to analyze the gating effect of the three residues. Through the molecular dynamics simulation of the complex structure between AhR LBD and different ligands, the ligand binding energy was changed according to the binding pattern of protein and ligand. The effects of different ligands on AhR LBD domain were analyzed in four aspects: protein structure change and binding cavity change. It was found that the mutation of three hydrophobic amino acid residues in Phe289 Tyr316Amino Ile319 would reduce the stability of the AhR ligand binding domain AhRLBD1, and play the role of a "gated" residue through hydrophobic connections. The overall structural analysis shows that the mutation near the binding cavity decreases the stability of the binding cavity, leads to obvious changes in flexibility and leads to the decrease of ligands activity and escape. By simulating AhR with different types of ligands, it was found that different ligands had different binding sites in the AhR LBD domain. However, some key amino acid residues, such as Phe289, Phe318GN 377, etc. These amino acid residues may have different conformations for different ligands to more closely align with small molecules and thus bind to small molecular ligands. We also found that amino acid residues Phe289 Ile319 and Met342 have high energy contribution to different ligands. At the same time, AhR can adjust its conformation and shape to suit the ligands with different structures. The main flexible motion occurs on A-B-loop and E-alpha. The results provide important theoretical basis for further understanding the mechanism of ligands acting on AhR protein, as well as for drug design, screening and product development targeting AhR protein.
【学位授予单位】：西南交通大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：Q50

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