Fig. 8: Dual-substrate binding scheme of DHB in CYP3A4.
From: Molecular dynamics simulations elucidate the role of the F–F′ loop in substrate entry into CYP3A4
a Top: Schematic representation illustrating the sequential binding of two DHB molecules and the associated conformational change of the F–F′ loop. Bottom: Overview of the MD simulations, with two distinct pathways leading to the dual DHB binding indicated by star symbols. b, c Left: Positional changes of the second DHB molecule (DHB2) as it binds to the active site of CYP3A4 in trajectories 3-7 (b) and 4-8 (c). The first bound DHB molecule is shown in green. Right: Time evolution of the Fe–C26 distance for DHB2 and the RMSD of the F–F′ loop during MD trajectories 3-7 (b) and 4-8 (c). Trajectory frames were aligned to the crystal structure before RMSD calculation. d, e F–F′ loop conformational changes during the simulations. Loops colored red, pink, light blue, and dark blue represent states I, II, III, and IV in b (d) or c (e), respectively. The overall enzyme structure is based on the crystal structure, with the F–F′ loop colored green. Final binding poses of the two DHB molecules in trajectories 3-7 (f) and 4-8 (g). The first DHB molecule is shown in pink, and the second in green. The distances between the heme iron and C26 on DHB are labeled in Å.
