Cytochrome P450 enzymes (CYPs) play an essential role in the bio-transformation of polychlorinated biphenyls (PCBs). The present work implemented quantum mechanic/molecular mechanic methods (QM/MM) and density functional theory (DFT) to study the metabolic activation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB136) catalyzed by CYP2B6. Electrophilic additions at the Cα and Cβ positions generate different active intermediates. The electrophilic addition energy barrier of Cβ is 10.9 kcal/mol higher than that of Cα, and Cα is the preferred site for the electrophilic addition reaction. Based on the previous experimental studies, this work investigated the mechanism of converting active intermediates into OH-PCB136, which has high toxicity in a non-enzymatic environment. Structural analysis via the electrostatic and noncovalent interactions indicates that Phe108, Ile114, Phe115, Phe206, Phe297, Ala298, Leu363, Val367, TIP32475 and TIP32667 play crucial roles in substrate recognition and metabolism. The analysis suggests that the halogen-π interactions are important factors for the metabolism of CYP2B6 to halogenated environmental pollutants. This work improved the understanding of the metabolism and activation process of chiral PCBs, and can be used as a guide to improve the microbial degradation efficiency of PCB136.
Keywords: Metabolic activation mechanism; OH-PCB; P450 enzyme; PCB; QM/MM.
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