Proximal Pocket Controls Alkene Oxidation Selectivity of Cytochrome P450 and Chloroperoxidase toward Small, Nonpolar Substrates

• Published in: The journal of physical chemistry. B Vol. 122; no. 32; pp. 7828 - 7838
• Main Authors: Chatfield, David C, Morozov, Alexander N
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.08.2018
• Subjects: Alkenes - chemistry; Catalytic Domain; Chloride Peroxidase - chemistry; Chloride Peroxidase - metabolism; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - metabolism; Hydrogen Bonding; Molecular Dynamics Simulation; Oxidation-Reduction; Quantum Theory; Substrate Specificity
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.8b04279

This paper examines the influence of the proximal pockets of cytochrome P450CAM and chloroperoxidase (CPO) on the relative favorability of catalytic epoxidation and allylic hydroxylation of olefins, a type of alkene oxidation selectivity. The study employs quantum mechanical models of the active site to isolate the proximal pocket’s influence on the barrier for the selectivity-determining step for each reaction, using cyclohexene and cis-β-methylstyrene as substrates. The proximal pocket is found to preference epoxidation by 2–5 kcal/mol, the largest value being for CPO, converting the active heme-thiolate moiety from being intrinsically hydroxylation-selective to being intrinsically epoxidation-selective. This theoretical study, the first to correctly predict these enzymes’ preference for epoxidation of allylic substrates, strongly suggests that the proximal pocket is the key determinant of alkene oxidation selectivity. The selectivity for epoxidation can be rationalized in terms of the proximal pocket’s modulation of the thiolate’s electron “push” and consequent influence on the heme redox potential and the basicity of the trans ligand.