Understanding and manipulating biosynthetic mechanisms for formation of terpenes relevant to human health - The Tantillo group applies modern computational chemistry to elucidate and manipulate the mechanisms by which terpenes (natural products derived from isoprene oligomers) and terpenoids (functionalized terpenes) are produced in nature. Techniques employed range from quantum chemistry to automated docking augmented by chemically meaningful constraints. The terpene/terpenoid class of natural products is the largest and most diverse in terms of both structures and biological activities relevant to humans (e.g., anti-cancer, anti-inflammatory, analgesic, anti-convulsive, anti-depressant, neuroprotective, anti-allergic, antibiotic, and others). The overall vision for the research program is to rationally expand the chemical space of terpenes and terpenoids using mechanistic insights obtained from computaional chemistry experiments, thereby providing new input for the testing and development of terpene-like compounds with potential new biological activities. A bottom-up modeling approach will be employed in which specific contributions to catalysis and selectivity are assessed using a series of theoretical experiments designed to reduce complicating factors (i.e., we will characterize inherent reactivity in the absence of an enzyme using quantum chemistry, then model specific enzyme-substrate interactions, then model the effect of active site shape using methods developed in-house that are specific for terpene synthases). Our predictions will be put to the test via synthesis of methyl- edited substrates and characterization of their reactions with terpene synthases we design. In addition to providing access to new terpene synthase enzymes that produce terpene-like molecules with new carbon skeletons and methylation patterns that can be tested for biological activity, this multi-step, multi-scale modeling approach will hopefully transform how computational studies on cyclization/rearrangement-promoting enzymes are generally carried out, in that it avoids the many issues associated with assessing contributions associated with specific effects from simulations that involve entire enzyme-substrate systems alone.
