Combined docking and molecular dynamics simulations to enlighten the capacity of Pseudomonas cepacia and Candida antarctica lipases to catalyze quercetin acetylation

A combined docking and molecular dynamics protocol was applied to investigate quercetin binding modes within the catalytic cavity of Candida antarctica lipase B (CALB) and Pseudomonas cepacia lipase (PCL), aiming to explain the difference of specificity of these enzymes in acetylation reaction. For both lipases, docking of quercetin yielded two families of conformers with either the quercetin A or B-ring pointing towards the catalytic residues. Molecular dynamics (MD) calculations were subsequently performed on several complexes of each family. MD trajectories were analyzed focusing on the orientation of the acyl donor bound to the catalytic serine towards the oxyanion hole residues and the proximity of quercetin hydroxyl groups to the catalytic residues. Results showed that with CALB, the acetate was not correctly positioned within the oxyanion hole whatever the orientation of quercetin, suggesting that no product could be obtained. With PCL, the acetate remained within the oxyanion hole during all MD trajectories. Depending on quercetin orientation, either the 7-OH group or the 3, 5, 3′, 4′-OH groups came alternatively near the catalytic residues, suggesting that all of them could be acylated. The capacity of models to explain the regioselectivity of the reaction was discussed. Key residues and interactions involved in quercetin binding modes were identified and related to the reaction feasibility.