title: Electrostatically guided dynamics--the root of fidelity in a promiscuous terpene synthase?
abstract: Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of more than 60,000 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. In the current study we present a detailed mechanistic view of the biosynthesis of the monoterpene bornyl diphosphate (BPP) from geranyl diphosphate by BPP synthase using state of the art simulation methods. We identify the bornyl cation as an enzyme-induced bifurcation point on the multidimensional free energy surface, connecting between the product BPP and the side product camphene. Chemical dynamics simulations suggest that the active site diphosphate moiety steers reaction trajectories toward product formation. Nonetheless, chemical dynamics is not precise enough for exclusive product formation, providing a rationale for the lack of fidelity in this promiscuous terpene cyclase.
authors.affiliation: Department of Chemistry and the Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel. majort@biu.ac.il
authors.forename: Dan Thomas
authors.initials: DT
authors.lastname: Major
authors.forename: Michal
authors.initials: M
authors.lastname: Weitman
mesh_terms: D019753:Intramolecular Lyases / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D055672:Static Electricity; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism
chemical_list: D013729:Terpenes; D019753:Intramolecular Lyases; C044526:geranyl-diphosphate cyclase