Deciphering Reaction Determinants of Altered-Activity CYP2D6 Variants by Well-Tempered Metadynamics Simulation and QM/MM Calculations.

The xenobiotic metabolizing enzyme CYP2D6 is the P450 cytochrome family member with the highest rate of polymorphism. This causes changes in the enzyme activity and specificity, which can ultimately lead to adverse reactions during drug treatment. To avoid or lower CYP-related toxicity risks, prediction of the most likely positions within a molecule where a metabolic reaction might occur is paramount. In order to obtain accurate predictions, it is crucial to understand all phenomena within the active site of the enzyme that contribute to an efficient substrate recognition and the subsequent catalytic reaction together with their relative weight within the overall thermodynamic context. This study aims to define the weight of the driving forces upon the C-H bond activation within CYP2D6 wild-type and a clinically relevant allelic variant with increased activity (