Nitric oxide binding to ferric cytochrome P450: A computational study

The interaction between nitric oxide (NO) and the active site of ferric cytochrome P450 was studied by means of density functional theory (DFT), at the generalized gradient approximation level, and of the SAM1 semiempirical method. The electrostatic effects of the protein environment were included i...

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Autores principales:	Scherlis, D.A., Cymeryng, C.B., Estrin, D.A.
Formato:	JOUR
Materias:	cytochrome P450 nitric oxide ferric ion protein water article catalysis chemical binding electron transport enzyme active site enzyme binding geometry quantum chemistry thermodynamics binding site chemical model chemistry computer simulation conformation drug antagonism metabolism X ray crystallography Binding Sites Computer Simulation Crystallography, X-Ray Cytochrome P-450 Enzyme System Ferric Compounds Models, Chemical Molecular Conformation Nitric Oxide Proteins Thermodynamics Water
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00201669_v39_n11_p2352_Scherlis
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00201669_v39_n11_p2352_Scherlis
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spelling	todo:paper_00201669_v39_n11_p2352_Scherlis2023-10-03T14:16:50Z Nitric oxide binding to ferric cytochrome P450: A computational study Scherlis, D.A. Cymeryng, C.B. Estrin, D.A. cytochrome P450 nitric oxide ferric ion protein water article catalysis chemical binding electron transport enzyme active site enzyme binding geometry quantum chemistry thermodynamics binding site chemical model chemistry computer simulation conformation drug antagonism metabolism X ray crystallography Binding Sites Computer Simulation Crystallography, X-Ray Cytochrome P-450 Enzyme System Ferric Compounds Models, Chemical Molecular Conformation Nitric Oxide Proteins Thermodynamics Water The interaction between nitric oxide (NO) and the active site of ferric cytochrome P450 was studied by means of density functional theory (DFT), at the generalized gradient approximation level, and of the SAM1 semiempirical method. The electrostatic effects of the protein environment were included in our DFT scheme by using a hybrid quantum classical approach. The active-site model consisted of an iron(III) porphyrin, the adjacent cysteine residue, and one coordinated water molecule. For this system, spin populations and relative energies for setected spin states were computed. Interestingly, the unpaired electron density, the HOMO, and the LUMO were found to be highly localized on the iron and in an appreciable extent on the sulfur coordinated to the metal. This provides central information about the reactivity of nitric oxide with the active site. Since the substitution of a molecule of H2O by NO has been proposed as being responsible for the inhibition of the cytochrome in the presence of nitric oxide, we have analyzed the thermodynamic feasibility of the ligand exchange process. The structure of the nitrosylated active site was partially optimized using SAM1. A low-spin ground state was obtained for the nitrosyl complex, with a linear Fe-N-O angle. The trends found in Fe-N-O angles and Fe-N lengths of the higher energy spin states provided a notable insight into the electronic configuration of the complex within the framework of the Enemark and Feltham formalism. In relation to the protein environment, it was assessed that the electrostatic field has significant effects on several computed properties. However, in both vacuum and protein environments, the ligand exchange reaction turned out to be exergonic and the relative orders of spin states of the relevant species were the same. Fil:Cymeryng, C.B. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00201669_v39_n11_p2352_Scherlis
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	cytochrome P450 nitric oxide ferric ion protein water article catalysis chemical binding electron transport enzyme active site enzyme binding geometry quantum chemistry thermodynamics binding site chemical model chemistry computer simulation conformation drug antagonism metabolism X ray crystallography Binding Sites Computer Simulation Crystallography, X-Ray Cytochrome P-450 Enzyme System Ferric Compounds Models, Chemical Molecular Conformation Nitric Oxide Proteins Thermodynamics Water
spellingShingle	cytochrome P450 nitric oxide ferric ion protein water article catalysis chemical binding electron transport enzyme active site enzyme binding geometry quantum chemistry thermodynamics binding site chemical model chemistry computer simulation conformation drug antagonism metabolism X ray crystallography Binding Sites Computer Simulation Crystallography, X-Ray Cytochrome P-450 Enzyme System Ferric Compounds Models, Chemical Molecular Conformation Nitric Oxide Proteins Thermodynamics Water Scherlis, D.A. Cymeryng, C.B. Estrin, D.A. Nitric oxide binding to ferric cytochrome P450: A computational study
topic_facet	cytochrome P450 nitric oxide ferric ion protein water article catalysis chemical binding electron transport enzyme active site enzyme binding geometry quantum chemistry thermodynamics binding site chemical model chemistry computer simulation conformation drug antagonism metabolism X ray crystallography Binding Sites Computer Simulation Crystallography, X-Ray Cytochrome P-450 Enzyme System Ferric Compounds Models, Chemical Molecular Conformation Nitric Oxide Proteins Thermodynamics Water
description	The interaction between nitric oxide (NO) and the active site of ferric cytochrome P450 was studied by means of density functional theory (DFT), at the generalized gradient approximation level, and of the SAM1 semiempirical method. The electrostatic effects of the protein environment were included in our DFT scheme by using a hybrid quantum classical approach. The active-site model consisted of an iron(III) porphyrin, the adjacent cysteine residue, and one coordinated water molecule. For this system, spin populations and relative energies for setected spin states were computed. Interestingly, the unpaired electron density, the HOMO, and the LUMO were found to be highly localized on the iron and in an appreciable extent on the sulfur coordinated to the metal. This provides central information about the reactivity of nitric oxide with the active site. Since the substitution of a molecule of H2O by NO has been proposed as being responsible for the inhibition of the cytochrome in the presence of nitric oxide, we have analyzed the thermodynamic feasibility of the ligand exchange process. The structure of the nitrosylated active site was partially optimized using SAM1. A low-spin ground state was obtained for the nitrosyl complex, with a linear Fe-N-O angle. The trends found in Fe-N-O angles and Fe-N lengths of the higher energy spin states provided a notable insight into the electronic configuration of the complex within the framework of the Enemark and Feltham formalism. In relation to the protein environment, it was assessed that the electrostatic field has significant effects on several computed properties. However, in both vacuum and protein environments, the ligand exchange reaction turned out to be exergonic and the relative orders of spin states of the relevant species were the same.
format	JOUR
author	Scherlis, D.A. Cymeryng, C.B. Estrin, D.A.
author_facet	Scherlis, D.A. Cymeryng, C.B. Estrin, D.A.
author_sort	Scherlis, D.A.
title	Nitric oxide binding to ferric cytochrome P450: A computational study
title_short	Nitric oxide binding to ferric cytochrome P450: A computational study
title_full	Nitric oxide binding to ferric cytochrome P450: A computational study
title_fullStr	Nitric oxide binding to ferric cytochrome P450: A computational study
title_full_unstemmed	Nitric oxide binding to ferric cytochrome P450: A computational study
title_sort	nitric oxide binding to ferric cytochrome p450: a computational study
url	http://hdl.handle.net/20.500.12110/paper_00201669_v39_n11_p2352_Scherlis
work_keys_str_mv	AT scherlisda nitricoxidebindingtoferriccytochromep450acomputationalstudy AT cymeryngcb nitricoxidebindingtoferriccytochromep450acomputationalstudy AT estrinda nitricoxidebindingtoferriccytochromep450acomputationalstudy
_version_	1782029724507176960

Nitric oxide binding to ferric cytochrome P450: A computational study

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