Title: Interpreting Polyketide Ketoreductase-Substrate Interactions Using Molecular Dynamics Simulation
Abstract: Polyketides are a large family of natural products including compounds with important bioactivities. Many of these compounds are pharmaceutically important and can act, for example, as antibiotic, anticancer, and antihypercholesterolemic agents. Polyketides are synthesized by multi-domain enzyme complex known as polyketide synthase (PKS), including reducing and non-reducing types. One of the essential steps of reducing-type polyketide synthesis is the regiospecific reduction of a single carbonyl group to a hydroxyl group catalyzed by ketoreductase (KR). The structure of the ketoreductases of several important reducing-type polyketides have been solved, including actinorhodin (ActKR), hedamycin (HedKR) and doxorubicin (DoxKR). However, the mechanism of ketoreductase-substrate interactions is still not well-known, due to the fact that poly-β-ketone intermediates, which is the substrate of ketoreductase, are highly reactive and prone to spontaneous cyclization, making it challenging to isolate. One solution to this problem is poly-β-ketone mimic, which is similar to poly-β-ketone intermediates in terms of both structures and chemical properties. Another solution is molecular dynamics simulation, which is a computer simulation method for studying the physical movements of atoms and molecules. In this study, both methods were used to interpret ketoreductase-substrate interactions. In particular, ActKR and HedKR were used as model ketoreductases and several potential factors of ketoreductase-substrate binding were identified, including substrate length, the presence of phosphate group on substrate, and two key residues in the binding pocket.