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浙江大学学报（理学版）
浙江大学学报（理学版）  2015, Vol. 42 Issue (6): 709-713    DOI: 10.3785/j.issn.1008-9497.2015.06.013
化学     
乙酰乳酸合成酶与抑制剂ZJ0777及CIE的分子对接和分子动力学模拟
Molecular docking and molecular dynamic simulations of inhibitor ZJ0777 and CIE binding to acetohydroxyacid synthases
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摘要： 乙酰乳酸合成酶（Acetohydroxyacid synthase，AHAS）是植物和微生物体内3种支链氨基酸生物合成过程中影响第1阶段的关键性酶，已被广泛证实为除草剂的靶标.ZJ0777是一种新型的除草剂，具有与传统商业除草剂相当的除草活性，且具有低毒、低残留、高选择性等优点.使用分子对接方法研究了AHASZJ0777复合物体系的作用模式，并与AHASCIE复合物晶体结构的作用模式作比较，发现二者的作用模式相似，对结合起关键作用的氨基酸均为Arg377，Trp574和Ser653.AHASCIE体系小分子蛋白质之间主要通过氢键相互作用，AHASZJ0777体系中小分子蛋白质之间主要通过ππ堆积相互作用.对分子对接得到的复合物AHASZJ0777及AHASCIE使用Amber程序进行1 135 ps的MD模拟实验，随后使用MMGBSA方法计算了抑制剂与蛋白质的结合能.结果表明，真空中的范德华力、静电作用和非极性溶剂化作用有利于抑制剂与AHAS的结合.本研究从理论上解释了新型ZJ0777分子的高效生物活性，为进一步设计和开发嘧啶苄胺类抑制剂提供了一定的理论指导.
关键词： 乙酰乳酸合成酶;  ZJ0777;  分子对接;  分子动力学模拟;  MM-GBSA    
Abstract: Acetohydroxyacid synthases（AHAS） which play an important role in biosynthesis of branched chain amino acid, are a group of enzymes widely distributed in plants and microorganism, and it is a popular target of many herbicides. ZJ0777 is a novel herbicide possessing many merits including low toxicity, low residue and high selectivity. The interaction between ZJ0777 and AHAS is studied via molecular docking using discovery studio program. The docking results indicate that ZJ0777 mainly interacts with residue Arg377, Trp574 and Ser653, which is very similar to the binding model of CIE in the crystal structure of AHASCIE complex. CIE has more hydrogen bond interactions with AHAS, and ZJ0777 has more ππ interactions with AHAS. AHASZJ0777 complex obtained by docking and AHASCIE complex are performed 1135 ps molecular dynamics (MD) simulations. RootMeanSquare deviation (RMSD) of the backbone atoms and the inhibitor atoms with respect to starting structure are calculated to estimate the quality and convergence of MD trajectory. The plots of RMSD as a function of simulation time imply that each system has reached stable and equilibrated state, thus it is reasonable to use these simulation data for further analysis. Binding free energy is calculated using MMGBSA method based on the last 200 snapshots of the MD trajectories. The results imply that the formation of the complex is mainly driven by gasphase Vander Walls interaction, gasphase electrostatic interaction and nonpolar solvation interaction. The mechanism of ZJ0777’s high biological activity is elucidated from theoretical perspective, which provides basis for the designing and optimizing of Pyrimidinyloxybenzylamine analogue inhibitors.
出版日期: 2015-07-01
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汪冒君
宣南霞
吴 军

引用本文:

汪冒君， 宣南霞， 吴 军. 乙酰乳酸合成酶与抑制剂ZJ0777及CIE的分子对接和分子动力学模拟[J]. 浙江大学学报（理学版）, 2015, 42(6): 709-713.

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https://www.zjujournals.com/sci/CN/Y2015/V42/I6/709

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