Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation

Abstract Cytochrome P450 reductase (CPR) is the key protein that regulates the electron transfer from NADPH to various heme-containing monooxygenases. CPR has two flavin-containing domains: one with flavin adenine dinucleotide (FAD), called FAD domain, and the other with flavin mononucleotide (FMN),...

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Autores principales:	Mikuru Iijima, Jun Ohnuki, Takato Sato, Masakazu Sugishima, Mitsunori Takano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d57eb9a9a2d54e228cf12d05af9f8ed4
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spelling	oai:doaj.org-article:d57eb9a9a2d54e228cf12d05af9f8ed42021-12-02T15:10:02ZCoupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation10.1038/s41598-019-45690-22045-2322https://doaj.org/article/d57eb9a9a2d54e228cf12d05af9f8ed42019-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-45690-2https://doaj.org/toc/2045-2322Abstract Cytochrome P450 reductase (CPR) is the key protein that regulates the electron transfer from NADPH to various heme-containing monooxygenases. CPR has two flavin-containing domains: one with flavin adenine dinucleotide (FAD), called FAD domain, and the other with flavin mononucleotide (FMN), called FMN domain. It is considered that the electron transfer occurs via FAD and FMN (NADPH → FAD → FMN → monooxygenase) and is regulated by an interdomain open-close motion. It is generally thought that the structural state is coupled with the redox state, which, however, has not yet been firmly established. In this report, we studied the coupling of the redox and the structural states by full-scale molecular dynamics (MD) simulation of CPR (total 86.4 μs). Our MD result showed that while CPR predominantly adopts the closed state both in the oxidized and reduced states, it exhibits a tendency to open in the reduced state. We also found a correlation between the FAD-FMN distance and the predicted FMN-monooxygenase distance, which is embedded in the equilibrium thermal fluctuation of CPR. Based on these results, a physical mechanism for the electron transfer by CPR is discussed.Mikuru IijimaJun OhnukiTakato SatoMasakazu SugishimaMitsunori TakanoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-8 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mikuru Iijima Jun Ohnuki Takato Sato Masakazu Sugishima Mitsunori Takano Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
description	Abstract Cytochrome P450 reductase (CPR) is the key protein that regulates the electron transfer from NADPH to various heme-containing monooxygenases. CPR has two flavin-containing domains: one with flavin adenine dinucleotide (FAD), called FAD domain, and the other with flavin mononucleotide (FMN), called FMN domain. It is considered that the electron transfer occurs via FAD and FMN (NADPH → FAD → FMN → monooxygenase) and is regulated by an interdomain open-close motion. It is generally thought that the structural state is coupled with the redox state, which, however, has not yet been firmly established. In this report, we studied the coupling of the redox and the structural states by full-scale molecular dynamics (MD) simulation of CPR (total 86.4 μs). Our MD result showed that while CPR predominantly adopts the closed state both in the oxidized and reduced states, it exhibits a tendency to open in the reduced state. We also found a correlation between the FAD-FMN distance and the predicted FMN-monooxygenase distance, which is embedded in the equilibrium thermal fluctuation of CPR. Based on these results, a physical mechanism for the electron transfer by CPR is discussed.
format	article
author	Mikuru Iijima Jun Ohnuki Takato Sato Masakazu Sugishima Mitsunori Takano
author_facet	Mikuru Iijima Jun Ohnuki Takato Sato Masakazu Sugishima Mitsunori Takano
author_sort	Mikuru Iijima
title	Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
title_short	Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
title_full	Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
title_fullStr	Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
title_full_unstemmed	Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation
title_sort	coupling of redox and structural states in cytochrome p450 reductase studied by molecular dynamics simulation
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/d57eb9a9a2d54e228cf12d05af9f8ed4
work_keys_str_mv	AT mikuruiijima couplingofredoxandstructuralstatesincytochromep450reductasestudiedbymoleculardynamicssimulation AT junohnuki couplingofredoxandstructuralstatesincytochromep450reductasestudiedbymoleculardynamicssimulation AT takatosato couplingofredoxandstructuralstatesincytochromep450reductasestudiedbymoleculardynamicssimulation AT masakazusugishima couplingofredoxandstructuralstatesincytochromep450reductasestudiedbymoleculardynamicssimulation AT mitsunoritakano couplingofredoxandstructuralstatesincytochromep450reductasestudiedbymoleculardynamicssimulation
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Coupling of Redox and Structural States in Cytochrome P450 Reductase Studied by Molecular Dynamics Simulation

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