Structural basis for cooperative binding of azoles to CYP2E1 as interpreted through guided molecular dynamics simulations

摘要: Abstract CYP2E1 metabolizes a wide array of small, hydrophobic molecules, resulting in their detoxification or activation into carcinogens through Michaelis–Menten as well cooperative mechanisms. Nevertheless, the molecular determinants for specificity and metabolic efficiency toward these compounds are still unknown. Herein, we employed computational docking studies coupled to dynamics simulations provide critical perspective understanding structural basis cooperativity observed an azoles from our previous binding catalytic (Hartman et al., 2014). The 28 complexes this study revealed common passageway that included steric barrier causing pause movement active site. entrance site acted like second sieve restrict access inner chamber. Collectively, interactions impacted final orientation reaching hence could explain differences biochemical properties studies, such consequences methylation at position 5 azole ring. association demonstrated significant stabilizing bound complex than first event. Intermolecular occurred between two residue side chains backbone involved both contacts hydrogen bonds. relative importance depended on structure respective indicating absence specific defining criteria unlike well-characterized dominant role hydrophobicity binding. Consequently, activity relationships described here elsewhere necessary more accurately identify factors impacting observation significance catalysis drugs, dietary compounds, pollutants.