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QM/MM Molecular Dynamics Investigations of the Substrate Binding of Leucotriene A4 Hydrolase: Implication for the Catalytic Mechanism
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2018-07-12 , DOI: 10.1021/acs.jpcb.8b04203
Xia Mu 1 , Dingguo Xu 1
Affiliation  

LTA4H is a monozinc bifunctional enzyme which exhibits both aminopeptidase and epoxide hydrolase activities. Its dual functions in anti- and pro-inflammatory roles have attracted wide attention to the inhibitor design. In this work, we tried to construct Michaelis complexes of LTA4H with both a native peptide substrate and LTA4 molecule using combined quantum mechanics and molecular mechanics molecular dynamics simulations. First of all, the zinc ion is coordinated by H295, H299, and E318. For its aminopeptidase activity, similar to conventional peptidases, the fourth ligand to the zinc ion is suggested to be an active site water, which is further hydrogen bonded with a downstream glutamic acid, E296. For the epoxide hydrolase activity, the fourth ligand to the zinc ion is found to be an epoxy oxygen atom. The potential of mean force calculation indicates about an 8.5 kcal/mol activation barrier height for the ring-opening reaction, which will generate a metastable carbenium intermediate. Subsequent frontier molecular orbital analyses suggest that the next step would be the nucleophilic attacking reaction at the C12 atom by a water molecule activated by D375. Our simulations also analyzed functions of several important residues like R563, K565, E271, Y383, and Y378 in the binding of peptide and LTA4.

中文翻译:

QM / MM分子动力学研究白三烯A4水解酶的底物结合:催化机制的意义。

LTA4H是一种单锌双功能酶,具有氨基肽酶和环氧化物水解酶的活性。它在抗炎和促炎作用中的双重功能引起了抑制剂设计的广泛关注。在这项工作中,我们尝试使用组合的量子力学和分子力学分子动力学模拟,构建具有天然肽底物和LTA4分子的LTA4H的Michaelis复合物。首先,锌离子由H295,H299和E318配位。对于其氨基肽酶活性,类似于常规的肽酶,锌离子的第四个配体被认为是活性位点水,该水进一步与下游的谷氨酸E296氢键合。对于环氧化物水解酶活性,发现锌离子的第四个配体是环氧氧原子。平均力计算的潜力表明,开环反应的活化壁垒高度约为8.5 kcal / mol,这将生成亚稳态的碳鎓中间体。随后的前沿分子轨道分析表明,下一步将是由D375活化的水分子在C12原子处进行亲核攻击反应。我们的模拟还分析了一些重要残基(如R563,K565,E271,Y383和Y378)在肽和LTA4结合中的功能。
更新日期:2018-07-14
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