Exploring Dihydroflavonol-4-reductase reactivity and selectivity by QM/MM-MD simulations

Flavonoids are secondary metabolites ubiquitously found in plants. Their antioxidant properties make them highly interesting natural compounds to be used in pharmacology. Therefore, unravelling the mechanisms of flavonoids biosynthesis is a current hot challenge for the scientific community. Among all the enzymes involved in this biosynthetic pathway, DihydroFlavonol-4-Reductase (DFR) plays a key role on the way to the production of anthocyanins and proanthocyanidins. Here, we provide new information on the mechanism of action of this enzyme by using QM/MM-MD simulations applied to both dihydroquercetin (DHQ) and dihydrokaempferol (DHK) substrates. The consideration of these very similar compounds shed light on the major role played by the enzyme on the stabilization of the transition state but also on the activation of the substrate before the reaction through Near-Attack Conformer effects.