title: The 'push' effect of the thiolate ligand in cytochrome P450: a theoretical gauging.
abstract: The 'push' effect of the thiolate ligand in cytochrome P450 is investigated using density functional calculations. Theory supports Dawson's postulate that the 'push' effect is crucial for the heterolytic O-O bond cleavage of ferric-peroxide, as well as for controlling the Fe(III)/Fe(II) redox process and gating the catalytic cycle. Two energetic factors that contribute to the 'push' effect are revealed. The dominant one is the field factor (DeltaE(field)=54-103 kcal/mol) that accounts for the classical electrostatic repulsion with the negative charge of thiolate. The smaller factor is a quantum mechanical effect (DeltaE(QM)(sigma)=39 kcal/mol, DeltaE(QM)(pi)=4 kcal/mol), which is associated with the sigma- and pi-donor capabilities of thiolate. The effects of ligand replacement, changes in hydrogen bonding and dielectric screening are discussed in term of these quantities. In an environment with a dielectric constant of 5.7, the total 'push' effect is reduced to 29-33 kcal/mol. Manifestations of the 'push' effect on other properties of thiolate enzymes are discussed.
authors.affiliation: Department of Organic Chemistry and the Lise Meitner--Minerva Center for Computational Quantum Chemistry, The Hebrew University, 91904 Jerusalem, Israel.
authors.forename: François
authors.initials: F
authors.lastname: Ogliaro
authors.forename: Samuël P
authors.initials: SP
authors.lastname: de Visser
authors.forename: Sason
authors.initials: S
authors.lastname: Shaik
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008962:Models, Theoretical; D010100:Oxygen / Q000378:metabolism; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism*
chemical_list: D008024:Ligands; D013438:Sulfhydryl Compounds; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D010100:Oxygen