The 'push' effect of the thiolate ligand in cytochrome P450: a theoretical gauging.
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.
Ogliaro
François
F
Department of Organic Chemistry and the Lise Meitner--Minerva Center for Computational Quantum Chemistry, The Hebrew University, 91904 Jerusalem, Israel.
de Visser
Samuël P
SP
Shaik
Sason
S
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*
D008024:Ligands; D013438:Sulfhydryl Compounds; D003577:Cytochrome P-450 Enzyme System; D006861:Hydrogen Peroxide; D010100:Oxygen