Complementary computational and experimental work is proposed to elucidate the biocatalytic properties of C. fumago chloroperoxidase (CCPO) and develop improved mutants for chiral synthesis. In particular, the work aims to determine the properties of CCPO's active site that lead to highly enantiospecific epoxidation using docking and MD computational techniques, and on that basis, to predict, synthesize, and assay mutants with improved enantiospecificity. Secondly, a QM and QM/MM study of the halogenation mechanism of CCPO is proposed in order to elucidate the mechanism, which has long been disputed. Halogenation is important for pharmaceutical synthesis and may also have significance for CCPO's epoxidation reaction. Both aspects of the proposed research will help construct synthetic routes to drugs with possible significant impact on human health.
|Pardillo, Armando D; Morozov, Alexander N; Chatfield, David C (2015) Proximal Pocket Hydrogen Bonds Significantly Influence the Mechanism of Chloroperoxidase Compound I Formation. J Phys Chem B 119:12590-602|
|Morozov, Alexander N; Pardillo, Armando D; Chatfield, David C (2015) Chloroperoxidase-Catalyzed Epoxidation of Cis-?-Methylstyrene: NH-S Hydrogen Bonds and Proximal Helix Dipole Change the Catalytic Mechanism and Significantly Lower the Reaction Barrier. J Phys Chem B 119:14350-63|
|Morozov, Alexander N; Roach, James P; Kotzer, Margarita et al. (2014) A possible mechanism for redox control of human neuroglobin activity. J Chem Inf Model 54:1997-2003|
|Zhang, Rui; He, Qinghao; Chatfield, David et al. (2013) Paramagnetic nuclear magnetic resonance relaxation and molecular mechanics studies of the chloroperoxidase-indole complex: insights into the mechanism of chloroperoxidase-catalyzed regioselective oxidation of indole. Biochemistry 52:3688-701|
|D'Cunha, Cassian; Morozov, Alexander N; Chatfield, David C (2013) Theoretical study of HOCl-catalyzed keto-enol tautomerization of ?-cyclopentanedione in an explicit water environment. J Phys Chem A 117:8437-48|
|Morozov, Alexander N; Chatfield, David C (2012) Chloroperoxidase-catalyzed epoxidation of cis-?-methylstyrene: distal pocket flexibility tunes catalytic reactivity. J Phys Chem B 116:12905-14|
|Morozov, Alexander N; D'Cunha, Cassian; Alvarez, Carlos A et al. (2011) Enantiospecificity of chloroperoxidase-catalyzed epoxidation: biased molecular dynamics study of a cis-?-methylstyrene/chloroperoxidase-compound I complex. Biophys J 100:1066-75|