As an important member of cytochrome P450 (CYP) enzymes, CYP17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones, making it an attractive therapeutic target. The emerging structural information about CYP17A1 and the growing number of inhibitors for these enzymes call for a systematic strategy to delineate and classify mechanisms of ligand transport through tunnels that control catalytic activity. In this work, we applied an integrated computational strategy to different CYP17A1 systems with a panel of ligands to systematically study at the atomic level the mechanism of ligand-binding and tunneling dynamics. Atomistic simulations and binding free energy computations identify the dynamics of dominant tunnels and characterize energetic properties of critical residues responsible for ligand binding. The common transporting pathways including S, 3, and 2c tunnels were identified in CYP17A1 binding systems, while the 2c tunnel is a newly formed pathway upon ligand binding. We employed and integrated several computational approaches including the analysis of functional motions and sequence conservation, atomistic modeling of dynamic residue interaction networks, and perturbation response scanning analysis to dissect ligand tunneling mechanisms. The results revealed the hinge-binding and sliding motions as main functional modes of the tunnel dynamic, and a group of mediating residues as key regulators of tunnel conformational dynamics and allosteric communications. We have also examined and quantified the mutational effects on the tunnel composition, conformational dynamics, and long-range allosteric behavior. The results of this investigation are fully consistent with the experimental data, providing novel rationale to the experiments and offering valuable insights into the relationships between the structure and function of the channel networks and a robust atomistic model of activation mechanisms and allosteric interactions in CYP enzymes.

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