QM/MM Analysis of Transition States and Transition State Analogues in Metalloenzymes.
QM/MM Analysis of Transition States and Transition State Analogues in Metalloenzymes.
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DOI：
10.1016/bs.mie.2016.05.016
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发表时间：
2016
影响因子：
--
通讯作者：
Cui Q
中科院分区：
文献类型：
--
作者：
Roston D;Cui Q
酶学正在进入一个许多问题可以从计算研究中受益的时代。虽然定量预测许多酶系统的行为仍然存在大量挑战，但通常来自计算的见解对于酶学界来说是重要的资产。在这里，我们为酶学家提供了关于对酶学机械问题最有用的计算类型的入门知识。特别是，我们强调从小型活性位点基序到完全溶剂化酶系统的模型整合，用于交叉验证和剖析酶环境的特定贡献。然后我们用碱性磷酸酶的案例研究来说明这些方法的具体应用。该案例研究涉及检查假定的过渡态类似物（钨酸盐和钒酸盐）与酶的结合模式。计算预测这些离子与酶亲核试剂的共价结合，并且它们采用预期过渡态的三角双锥几何形状。通过将这些结构与通过自由能模拟发现的过渡态进行比较，我们评估了过渡态类似物模拟真实过渡态的程度。讨论期间还强调了值得谨慎对待的技术问题以及金属酶定量分析的几个剩余挑战。
Enzymology is approaching an era where many problems can benefit from computational studies. While ample challenges remain in quantitatively predicting behavior for many enzyme systems, the insights that often come from computations are an important asset for the enzymology community. Here we provide a primer for enzymologists on the types of calculations that are most useful for mechanistic problems in enzymology. In particular, we emphasize the integration of models that range from small active site motifs to fully solvated enzyme systems for cross-validation and dissection of specific contributions from the enzyme environment. We then use a case study of the enzyme alkaline phosphatase to illustrate specific application of the methods. The case study involves examination of the binding modes of putative transition state analogues (tungstate and vanadate) to the enzyme. The computations predict covalent binding of these ions to the enzymatic nucleophile and that they adopt the trigonal bipyramidal geometry of the expected transition state. By comparing these structures with transition states found through free energy simulations, we assess the degree to which the transition state analogues mimic the true transition states. Technical issues worth treating with care as well as several remaining challenges to quantitative analysis of metalloenzymes are also highlighted during the discussion.
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影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
16.6
作者：
Claeyssens, Frederik;Harvey, Jeremy N.;Werner, Hans-Joachim
通讯作者：
Werner, Hans-Joachim
影响因子：
8
作者：
Alberts, IL;Nadassy, K;Wodak, SJ
通讯作者：
Wodak, SJ
影响因子：
64.8
作者：
Blomberg, Rebecca;Kries, Hajo;Hilvert, Donald
通讯作者：
Hilvert, Donald