Catalytic control in terpenoid cyclases: Multiscale modeling of thermodynamic, kinetic, and dynamic effects

In this Opinion we review some of the key work on terpene biosynthesis using multi-scale simulation approaches. Terpene synthases generate terpenes employing beautiful and rich carbocation chemistry, including highly specific ring formations, hydride, proton, methyl, and methylene migrations, followed by reaction quenching. In spite of the chemical finesse of these enzymes, terpene synthases are highly promiscuous. Incidentally, these mischievous enzymes are very challenging to treat computationally due to the inherent complexity of the potential energy surface in carbocations and the lack of directional hydrogen bonds to active site residues. Thus, a carefully designed computational platform must be employed. Herein, we review multi-scale simulations of squalene-hopene, aristolochene, and bornyl diphosphate synthases, and highlight what we have learned from this work.