Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• Cytochrome P450 2B4 (CYP 2B4) is a model enzyme for understanding drug metabolism by microsomal class II CYPs.
• CYP 2B4 exhibits conformational flexibility, with crystal structures showing open or closed active site cavities.

Purpose of the Study:

• To investigate the conformational ensemble of full-length CYP 2B4 within a phospholipid bilayer.
• To elucidate the role of enzyme conformation in substrate binding, product release, and inhibitor interactions.

Main Methods:

• Multiresolution molecular dynamics (MD) simulations, including coarse-grained and atomistic resolutions.
• Analysis of enzyme tunnels (CAVER), water routes (AquaDuct), and ligand dissociation (Random Acceleration MD).

Main Results:

• Two predominant orientations of CYP 2B4 in the bilayer were identified.
• Open conformations facilitate ligand access to the heme site, while closed conformations prolong residence times.
• Conformation-dependent passage of molecules through tunnels and water channels was observed.

Conclusions:

• The open CYP 2B4 conformation facilitates substrate/product exchange with the membrane.
• The closed conformation enhances substrate/inhibitor residence time and selective passage of small molecules.
• Transient hydrophobic pockets in the open conformation may influence substrate binding or allosteric regulation.