title: Active-site residues move independently from the rest of the protein in a 200 ns molecular dynamics simulation of cytochrome P450 CYP119.
abstract: The conformational dynamics of cytochrome P450 enzymes are critical to their catalytic activity. In this study, the correlated motion between residues in a 200 ns molecular dynamics trajectory of the thermophilic CYP119 was analyzed to parse out conformational relationships. Residues that are structurally related, for example residues within a helix, generally have highly correlated motion. In addition, clusters of non-adjacent residues that show correlated motion ("hot spots") are seen in various regions, including at the base of the F and G helices that make up the most dynamic region of the enzyme. A modified k-means algorithm that clusters residues based on their correlated motion indicates that functionally related residues are in the same cluster (e.g., the catalytic threonines and the heme). Tightly coupled clusters form a solvent-exposed "shell" around the enzyme, whereas less coupling between clusters is seen in regions that are critical to ligand interactions, redox partner interactions, and catalysis. Most notably, we find that residues in the active site move independently from the rest of the enzyme, effectively insulating the catalytic machinery from other regions of the protein.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158-2517, USA.
authors.forename: Relly
authors.initials: R
authors.lastname: Brandman
authors.forename: Jed N
authors.initials: JN
authors.lastname: Lampe
authors.forename: Yigal
authors.initials: Y
authors.lastname: Brandman
authors.forename: Paul R Ortiz
authors.initials: PR
authors.lastname: de Montellano
mesh_terms: D019843:Archaeal Proteins / Q000737:chemistry*; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D016945:Sulfolobus acidocaldarius / Q000201:enzymology*
chemical_list: D019843:Archaeal Proteins; D003577:Cytochrome P-450 Enzyme System; C408874:CYP119 protein, Sulfolobus solfataricus