Predicting Productive Binding Modes for Substrates and Carbocation Intermediates in Terpene Synthases—Bornyl Diphosphate Synthase As a Representative Case,ACS Catalysis

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Predicting Productive Binding Modes for Substrates and Carbocation Intermediates in Terpene Synthases—Bornyl Diphosphate Synthase As a Representative Case
ACS Catalysis ( IF 11.3 ) Pub Date : 2018-03-08 00:00:00 , DOI: 10.1021/acscatal.8b00342
Terrence E. O’Brien ₁ , Steven J. Bertolani ₁ , Yue Zhang ₁ , Justin B. Siegel _{1,

2,

3} , Dean J. Tantillo ₁

Affiliation

Terpene synthases comprise a family of enzymes that convert acyclic oligo-isoprenyl diphosphates to terpene natural products with complex, polycyclic carbon backbones via the generation and protection of carbocation intermediates. To accommodate this chemistry, terpene synthase active sites generally are lined with alkyl and aromatic, i.e., nonpolar, side chains. Predicting the correct, mechanistically relevant binding modes for entire terpene synthase reaction pathways remains an unsolved challenge. Here, we describe a method for identifying such modes: TerDockin, a series of protocols to predict the orientation of carbon skeletons of substrates and derived carbocations relative to the bound diphosphate group in terpene synthase active sites. Using this recipe for bornyl diphosphate synthase, we have predicted binding modes that are consistent with all current experimental observations, including the results of isotope labeling experiments and known stereoselectivity. In addition, the predicted binding modes recapitulate key findings of a seminal study involving more computationally demanding QM/MM molecular dynamics methods on part of this pathway. This work illustrates the value of the TerDockin approach as a starting point for more involved calculations and sets the stage for the rational engineering of this family of enzymes.

中文翻译：

预测萜烯合酶中底物和碳正离子中间体的生产性结合模式-代表性的案例是二磷酸苄基合酶

萜烯合酶包含一族酶，该酶通过碳正离子中间体的产生和保护将无环的低聚异戊二烯基二磷酸转化为具有复杂的多环碳骨架的萜烯天然产物。为了适应这种化学反应，萜烯合酶活性位点通常衬有烷基和芳族侧链，即非极性侧链。预测整个萜烯合酶反应途径的正确的，机械相关的结合方式仍然是一个尚未解决的挑战。在这里，我们描述一种识别这种模式的方法：TerDockin，一系列协议可预测底物和衍生的碳正离子的碳骨架相对于萜烯合酶活性位点中结合的二磷酸基团的方向。使用该配方的冰片基二磷酸合酶，我们预测了与所有当前实验观察结果一致的结合模式，包括同位素标记实验的结果和已知的立体选择性。此外，预测的结合模式概括了一项开创性研究的关键发现，该开创性研究涉及该途径的一部分，在计算上要求更高的QM / MM分子动力学方法。这项工作说明了TerDockin方法作为更复杂的计算起点的价值，并为合理设计该酶家族奠定了基础。

更新日期：2018-03-08

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