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CO migration pathways in cytochrome P450_cam studied by molecular dynamics simulations

¹ Inserm U759, Institut Curie-Recherche, Bâtiment 112, Université Paris-Sud, 91405 Orsay cedex, France
² Institut Curie-Recherche, Bâtiment 112, Université Paris-Sud, 91405 Orsay cedex, France
³ Institut de Biochimie et Biophysique Moléculaire et Cellulaire, CNRS UMR8619, Université Paris-Sud, 91405 Orsay cedex, France

(RECEIVED May 31, 2006; FINAL REVISION January 24, 2007; ACCEPTED January 26, 2007)

Previous laser flash photolysis investigations between 100 and 300 K have shown that the kinetics of CO rebinding with cytochrome P450_cam(camphor) consist of up to four different processes revealing a complex internal dynamics after ligand dissociation. In the present work, molecular dynamics simulations were undertaken on the ternary complex P450_cam(cam)(CO) to explore the CO migration pathways, monitor the internal cavities of the protein, and localize the CO docking sites. One trajectory of 1 nsec with the protein in a water box and 36 trajectories of 1 nsec in the vacuum were calculated. In each trajectory, the protein contained only one CO ligand on which no constraints were applied. The simulations were performed at 200, 300, and 320 K. The results indicate the presence of seven CO docking sites, mainly hydrophobic, located in the same moiety of the protein. Two of them coincide with xenon binding sites identified by crystallography. The protein matrix exhibits eight persistent internal cavities, four of which corresponding to the ligand docking sites. In addition, it was observed that water molecules entering the protein were mainly attracted into the polar pockets, far away from the CO docking sites. Finally, the identified CO migration pathways provide a consistent interpretation of the experimental rebinding kinetics.

Keywords: internal cavities; ligand migration; molecular dynamics; docking sites; ligand rebinding kinetics

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.062374707.

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