ICS84

Invited
Multiscale modeling of complex enzyme reactions: From consensus docking to free energy simulations

Dan T. Major Susanta Das Anil R. Mhashal Keren Raz Shani Levi Efrat Pahima Mor Shimshi
Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel

Accurate modeling of enzyme reactions is a daunting task and requires a carefully designed computational protocol that relies on well-established theoretical foundations. Key features of enzyme modeling protocols include accurate potential energy surfaces, multi-scale methods, enhanced docking approaches, and free energy simulations. Here we will describe advanced enzyme modeling protocols that are particularly useful in the modeling of complex, multistep reactions in natural product biosynthesis. In particular, we will describe a new docking program, dubbed EnzyDock, which facilitates multiscale and multistate docking. We will show how such an advanced multiscale modeling protocol can be applied in the study of natural product formation in terpene synthases, which are responsible for the initial cyclization cascade in the generation of more than 80,000 known natural products. This abundance of compounds is generated using a very limited pool of substrates based on linear isoprenoids. The astounding chemodiversity obtained by terpene cyclases suggests a tremendous catalytic challenge to these often-promiscuous enzymes. Here, we will focus on representative enzymes that have been studied in our group, as well as enzyme-mimicking nano-capsules. We will describe a novel view of enzyme catalysis based on the biosynthesis of these terpene synthases. We will also show how one can harness the immense synthetic potential of enzymes in terpene biosynthetic pathways for the construction of novel natural-products with uses in medicine, agriculture, and personal care.1-5

Simultaneous docking of substrate, intermediates, and product in an enzyme active site.

  1. Major, D. T.; Weitmann, M. J. Am. Chem. Soc. 2012, 314, 19454.
  2. Major, D. T.; Freud, Y.; Weitman, M. Curr. Opin. Chem. Biol. 2014, 21, 25.
  3. Dixit, M.; Weitman, M.; Gao, J.; Major, D. T. ACS Catal. 2017, 7, 812.
  4. Driller, R.; Janke, S.; Fuchs, M.; Warner, E.; Mhashal, A. R.; Major, D. T.; Christmann, M.; Brück, T.; Loll, B. Nat. Commun. 2018, 9, 3971.
  5. Major, D. T. Nat. Catal. 2018, 1, 567.








Powered by Eventact EMS