Identification of structural properties influencing the metabolism of polycyclic aromatic hydrocarbons by cytochrome P450 1A1

Highlights: • Build QSAR models to predict binding, metabolism and mutagenicity of PAHs by CYP1A1 • Identify the key properties of PAH metabolism by CYP1A1 based on QSAR and tests • van der Waals interactions (glide vdw) are essential for PAH binding to CYP1A1. • Fe_Cmin and heme vdw influence the metabolic clearance of PAHs by CYP1A1. • ESP neg variance affects the mutagenicity of PAHs via epoxides formation by CYP1A1 Cytochrome P450 1A1 (CYP1A1) has served as a known metabolic enzyme that mediates the carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). However, the structural mechanism involved in the metabolic capacity remains unclear. In this study, thirty-three calculated properties representing the physicochemical and electronic properties of PAH and PAH-CYP1A1 interactions were utilized to identify the key structural properties that affect metabolic processes, including binding ability, metabolic clearance, and mutagenicity, using a quantitative structure-activity relationship (QSAR) strategy combined with docking methods, QM/MM calculations and ab initio calculations. van der Waals interactions (glide vdw) appeared to be important for PAH binding to CYP1A1 and were mainly affected by the molecular weight and hydrophobic structures of PAHs. Interaction features between PAHs and heme, including the distance between iron and carbons of PAHs (Fe_Cmin) and heme vdw, coordinately influence the metabolic clearance of PAHs. Furthermore, the electronic properties (ESP neg variance) appeared to be critical for the mutagenicity of PAHs by CYP1A1 through influencing epoxide metabolite formation. The QSAR models with these key properties provide a new perspective on the structural mechanism of PAH metabolism and provide a useful in silico tool for screening, classifying and predicting PAHs for their metabolism-related toxicities and risk assessment in the environment.