Computational simulations of structural role of the active-site W374C mutation of acetyl-coenzyme-A carboxylase: Multi-drug resistance mechanism
Computational simulations of structural role of the active-site W374C mutation of acetyl-coenzyme-A carboxylase: Multi-drug resistance mechanism
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DOI：
10.1007/s00894-010-0742-4
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发表时间：
2011-03
影响因子：
2.2
通讯作者：
Xiao-Lei Zhu;Wenchao Yang;Ning-Xi Yu;Sheng-Gang Yang;Guangfu Yang
中科院分区：
文献类型：
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作者：
Xiao-Lei Zhu;Wenchao Yang;Ning-Xi Yu;Sheng-Gang Yang;Guangfu Yang
针对草类可塑性乙酰辅酶A羧基酶(ACCase，EC 6.4.1.2)的除草剂对除草剂有选择性的抑制作用。这种除草剂家族在世界范围内的广泛使用已经在许多草本植物中选择了抗性基因。最近，活性部位W374C突变被发现对氟乐磷(HF)、非诺沙普(FR)、敌敌畏(DF)和氯地诺(CF)异烟肼产生多重耐药。肌瘤。为了揭示W374C突变引起的抗性机制，本工作通过分子对接和分子动力学模拟研究了上述四种除草剂与野生型和突变型ACCase的结合。结合自由能用分子力学-泊松-玻尔兹曼表面积(MM/PBSA)方法计算。四种除草剂的结合自由能计算值与IC50值的实验顺序定性一致。所有的计算模型和能量结果表明，W374C突变对结合口袋的构象变化和配体-蛋白质相互作用有很大的影响。最显著的构象变化与芳香族氨基酸残基有关，如Phe377、Tyr161‘和Trp346。结果表明，突变后对结合亲和力有重要贡献的Phe377和Tyr161‘残基与配体之间的π-π相互作用减弱，与突变型ACCase的结合亲和力低于野生型，这是除草剂产生抗药性的分子基础。从计算模拟中获得的结构作用和机制洞察将为合理设计新型抑制剂以克服与W374C突变相关的耐药性提供新的起点。
Herbicides targeting grass plastidic acetyl-CoA carboxylase (ACCase, EC 6.4.1.2) are selectively effective against graminicides. The intensive worldwide use of this herbicide family has selected for resistance genes in a number of grass weed species. Recently, the active-site W374C mutation was found to confer multi-drug resistance toward haloxyfop (HF), fenoxaprop (FR), Diclofop (DF), and clodinafop (CF) inA. myosuroides. In order to uncover the resistance mechanism due to W374C mutation, the binding of above-mentioned four herbicides to both wild-type and the mutant-type ACCase was investigated in the current work by molecular docking and molecular dynamics (MD) simulations. The binding free energies were calculated by molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) method. The calculated binding free energy values for four herbicides were qualitatively consistent with the experimental order of IC50values. All the computational model and energetic results indicated that the W374C mutation has great effects on the conformational change of the binding pocket and the ligand-protein interactions. The most significant conformational change was found to be associated with the aromatic amino acid residues, such as Phe377, Tyr161′ and Trp346. As a result, the π-π interaction between the ligand and the residue of Phe377 and Tyr161′, which make important contributions to the binding affinity, was decreased after mutation and the binding affinity for the inhibitors to the mutant-type ACCase was less than that to the wild-type enzyme, which accounts for the molecular basis of herbicidal resistance. The structural role and mechanistic insights obtained from computational simulations will provide a new starting point for the rational design of novel inhibitors to overcome drug resistance associated with W374C mutation.