Computational study on the metabolic activation mechanism of PeCDD by Cytochrome P450 1A1

Cytochrome P450 enzymes (CYPs) are crucial for metabolizing dioxin compounds such as 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD). Here we have applied molecular dynamic simulations (MD), quantum mechanics/molecular mechanics methods (QM/MM) and density functional theory (DFT) to investigate the metabolic activation and transformation of PeCDD catalyzed by CYP1A1. Our QM/MM calculations highlight that PeCDD can be activated by P450s through the well-known electrophilic addition mechanism with an average energy barrier of 20.9 kcal/mol. Based on the results of previous experimental studies, further conversions of ketone products and epoxidation products that are mediated by P450 enzymes were investigated through DFT calculations. Analysis of the structures via the noncovalent interactions (NCI) method and the distortion-interaction model suggests that amino acids Ser122, Ala317, Ile386 and Leu496 play important roles in the metabolic process.