EnzyDock: Protein–Ligand Docking of Multiple Reactive States along a Reaction Coordinate in Enzymes,Journal of Chemical Theory and Computation

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EnzyDock: Protein–Ligand Docking of Multiple Reactive States along a Reaction Coordinate in Enzymes
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2019-08-06 00:00:00 , DOI: 10.1021/acs.jctc.9b00366
Susanta Das ₁ , Mor Shimshi ₁ , Keren Raz ₁ , Neta Nitoker Eliaz ₁ , Anil Ranu Mhashal ₁ , Tamar Ansbacher _{1,

2} , Dan T. Major ₁

Affiliation

Enzymes play a pivotal role in all biological systems. These biomachines are the most effective catalysts known, dramatically enhancing the rate of reactions by more than 10 orders of magnitude relative to the uncatalyzed reactions in solution. Predicting the correct, mechanistically appropriate binding modes for substrate and product, as well as all reaction intermediates and transition states, along a reaction pathway is immensely challenging and remains an unsolved problem. In the present work, we developed an effective methodology for identifying probable binding modes of multiple ligand states along a reaction coordinate in an enzyme active site. The program is called EnzyDock and is a CHARMM-based multistate consensus docking program that includes a series of protocols to predict the chemically relevant orientation of substrate, reaction intermediates, transition states, product, and inhibitors. EnzyDock is based on simulated annealing molecular dynamics and Monte Carlo sampling and allows ligand, as well as enzyme side-chain and backbone flexibility. The program can employ many user-defined constraints and restraints and classical force field potentials, as well as a range of hybrid quantum mechanics-molecular mechanics potentials. Herein, we apply EnzyDock to several different kinds of problems. First, we study two terpene synthase reactions, namely bornyl diphosphate synthase and the bacterial diterpene synthase CotB2. Second, we use EnzyDock to predict reaction coordinate states in a pair of Diels–Alder reactions in the enzymes spirotetronate AbyU and LepI. Third, we study a couple of racemases: the cofactor-dependent serine racemase and the cofactor independent proline racemase. Finally, we study several cases of covalent docking involving the Michael addition reaction. For all systems we predict binding modes that are consistent with available experimental observations, as well as with theoretical modeling studies from the literature. EnzyDock provides a platform for generating mechanistic insight into enzyme reactions, useful and reliable starting points for in-depth multiscale modeling projects, and rational design of noncovalent and covalent enzyme inhibitors.

中文翻译：

EnzyDock：沿反应坐标的多个反应态的蛋白质-配体对接

酶在所有生物系统中都起着至关重要的作用。这些生物机械是已知的最有效的催化剂，相对于溶液中未催化的反应，其反应速率显着提高了10个数量级以上。沿着反应路径预测底物和产物以及所有反应中间体和过渡态的正确的，机械学上合适的结合方式是巨大的挑战，并且仍然是一个未解决的问题。在目前的工作中，我们开发了一种有效的方法，用于确定沿着酶活性位点中反应坐标的多个配体状态的可能结合模式。该程序称为EnzyDock，是基于CHARMM的多状态共识对接程序，其中包括一系列协议，可预测底物的化学相关方向，反应中间体，过渡态，产物和抑制剂。EnzyDock基于模拟的退火分子动力学和蒙特卡洛采样，并允许配体以及酶的侧链和主链柔性。该程序可以使用许多用户定义的约束和约束以及经典的力场电势，以及一系列混合量子力学-分子力学电势。在这里，我们将EnzyDock应用于几种不同类型的问题。首先，我们研究了两个萜烯合酶反应，即冰片基二磷酸合酶和细菌二萜合酶CotB2。其次，我们使用EnzyDock来预测螺旋体AbyU和LepI酶在一对Diels-Alder反应中的反应坐标状态。第三，我们研究了两个消旋体：辅因子依赖性丝氨酸消旋酶和辅因子依赖性脯氨酸消旋酶。最后，我们研究了涉及迈克尔加成反应的共价对接的几种情况。对于所有系统，我们预测与可用的实验观察以及文献中的理论建模研究一致的结合模式。EnzyDock提供了一个平台，用于生成对酶反应的机理性见解，深入多尺度建模项目的有用且可靠的起点以及合理设计非共价和共价酶抑制剂的方法。

更新日期：2019-08-06

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