Molecular mechanism of myoglobin autoxidation: Insights from computer simulations

Myoglobin (Mb) and hemoglobin have the biological ability to carry/store oxygen (O2), a property which requires its heme iron atom to be in the ferrous -Fe(II)- state. However, the thermodynamically stable state in the presence of O2 is Fe(III) and thus the oxidation rate of a globin is a critical p...

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Autores principales:	Rosi, Pablo Eduardo, Petruk, Ariel Alcides, Martí, Marcelo Adrián, Estrin, Dario Ariel
Publicado:	2015
Materias:	Amino acids Hemoglobin Hydrogen bonds Iron compounds Oxygen Porphyrins Protonation Rate constants Acid catalysis Basic mechanism Hydroxide anions Molecular mechanism Oxidation rates Simulation methodology State of the art Thermodynamically stable Oxidation heme myoglobin oxygen catalysis chemistry computer simulation genetics hydrogen bond metabolism molecular dynamics mutation oxidation reduction reaction quantum theory thermodynamics Catalysis Computer Simulation Heme Hydrogen Bonding Molecular Dynamics Simulation Mutation Myoglobin Oxidation-Reduction Quantum Theory Thermodynamics
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10895639_v119_n5_p1802_Arcon http://hdl.handle.net/20.500.12110/paper_10895639_v119_n5_p1802_Arcon
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_10895639_v119_n5_p1802_Arcon
record_format	dspace
spelling	paper:paper_10895639_v119_n5_p1802_Arcon2023-06-08T16:06:35Z Molecular mechanism of myoglobin autoxidation: Insights from computer simulations Rosi, Pablo Eduardo Petruk, Ariel Alcides Martí, Marcelo Adrián Estrin, Dario Ariel Amino acids Hemoglobin Hydrogen bonds Iron compounds Oxygen Porphyrins Protonation Rate constants Acid catalysis Basic mechanism Hydroxide anions Molecular mechanism Oxidation rates Simulation methodology State of the art Thermodynamically stable Oxidation heme myoglobin oxygen catalysis chemistry computer simulation genetics hydrogen bond metabolism molecular dynamics mutation oxidation reduction reaction quantum theory thermodynamics Catalysis Computer Simulation Heme Hydrogen Bonding Molecular Dynamics Simulation Mutation Myoglobin Oxidation-Reduction Oxygen Quantum Theory Thermodynamics Myoglobin (Mb) and hemoglobin have the biological ability to carry/store oxygen (O2), a property which requires its heme iron atom to be in the ferrous -Fe(II)- state. However, the thermodynamically stable state in the presence of O2 is Fe(III) and thus the oxidation rate of a globin is a critical parameter related to its function. Mb has been extensively studied and many mutants have been characterized regarding its oxygen mediated oxidation (i.e., autoxidation) rates. Site directed mutants in residues 29 (B10), which shapes the distal cavity, and 64 (E7), the well-known histidine gate, have been shown to display a wide range of autoxidation rate constants. In this work, we have thoroughly studied the mechanism underlying the autoxidation process by means of state-of-the-art computer simulation methodologies, using Mb and site directed mutants as benchmark cases. Our results explain the observed autoxidation rate tendencies in different variants of Mb, L29F < wt < L29A = H64Q < H64F < H64A, and shed light on several aspects of the reaction at the atomic level. First, water access to the distal pocket is a key event and the observed acid catalysis relies on HisE7 protonation and opening of the His gate to allow water access, rather than protonation of the oxy heme itself. Our results also suggest that the basic mechanism, i.e., superoxide displacement by hydroxide anion, is energetically more feasible. Finally, we confirmed that distal hydrogen bonds protect the oxy complex from autoxidation. © 2015 American Chemical Society. Fil:Rosi, P. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Petruk, A.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Marti, M.A. 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. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10895639_v119_n5_p1802_Arcon http://hdl.handle.net/20.500.12110/paper_10895639_v119_n5_p1802_Arcon
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Amino acids Hemoglobin Hydrogen bonds Iron compounds Oxygen Porphyrins Protonation Rate constants Acid catalysis Basic mechanism Hydroxide anions Molecular mechanism Oxidation rates Simulation methodology State of the art Thermodynamically stable Oxidation heme myoglobin oxygen catalysis chemistry computer simulation genetics hydrogen bond metabolism molecular dynamics mutation oxidation reduction reaction quantum theory thermodynamics Catalysis Computer Simulation Heme Hydrogen Bonding Molecular Dynamics Simulation Mutation Myoglobin Oxidation-Reduction Oxygen Quantum Theory Thermodynamics
spellingShingle	Amino acids Hemoglobin Hydrogen bonds Iron compounds Oxygen Porphyrins Protonation Rate constants Acid catalysis Basic mechanism Hydroxide anions Molecular mechanism Oxidation rates Simulation methodology State of the art Thermodynamically stable Oxidation heme myoglobin oxygen catalysis chemistry computer simulation genetics hydrogen bond metabolism molecular dynamics mutation oxidation reduction reaction quantum theory thermodynamics Catalysis Computer Simulation Heme Hydrogen Bonding Molecular Dynamics Simulation Mutation Myoglobin Oxidation-Reduction Oxygen Quantum Theory Thermodynamics Rosi, Pablo Eduardo Petruk, Ariel Alcides Martí, Marcelo Adrián Estrin, Dario Ariel Molecular mechanism of myoglobin autoxidation: Insights from computer simulations
topic_facet	Amino acids Hemoglobin Hydrogen bonds Iron compounds Oxygen Porphyrins Protonation Rate constants Acid catalysis Basic mechanism Hydroxide anions Molecular mechanism Oxidation rates Simulation methodology State of the art Thermodynamically stable Oxidation heme myoglobin oxygen catalysis chemistry computer simulation genetics hydrogen bond metabolism molecular dynamics mutation oxidation reduction reaction quantum theory thermodynamics Catalysis Computer Simulation Heme Hydrogen Bonding Molecular Dynamics Simulation Mutation Myoglobin Oxidation-Reduction Oxygen Quantum Theory Thermodynamics
description	Myoglobin (Mb) and hemoglobin have the biological ability to carry/store oxygen (O2), a property which requires its heme iron atom to be in the ferrous -Fe(II)- state. However, the thermodynamically stable state in the presence of O2 is Fe(III) and thus the oxidation rate of a globin is a critical parameter related to its function. Mb has been extensively studied and many mutants have been characterized regarding its oxygen mediated oxidation (i.e., autoxidation) rates. Site directed mutants in residues 29 (B10), which shapes the distal cavity, and 64 (E7), the well-known histidine gate, have been shown to display a wide range of autoxidation rate constants. In this work, we have thoroughly studied the mechanism underlying the autoxidation process by means of state-of-the-art computer simulation methodologies, using Mb and site directed mutants as benchmark cases. Our results explain the observed autoxidation rate tendencies in different variants of Mb, L29F < wt < L29A = H64Q < H64F < H64A, and shed light on several aspects of the reaction at the atomic level. First, water access to the distal pocket is a key event and the observed acid catalysis relies on HisE7 protonation and opening of the His gate to allow water access, rather than protonation of the oxy heme itself. Our results also suggest that the basic mechanism, i.e., superoxide displacement by hydroxide anion, is energetically more feasible. Finally, we confirmed that distal hydrogen bonds protect the oxy complex from autoxidation. © 2015 American Chemical Society.
author	Rosi, Pablo Eduardo Petruk, Ariel Alcides Martí, Marcelo Adrián Estrin, Dario Ariel
author_facet	Rosi, Pablo Eduardo Petruk, Ariel Alcides Martí, Marcelo Adrián Estrin, Dario Ariel
author_sort	Rosi, Pablo Eduardo
title	Molecular mechanism of myoglobin autoxidation: Insights from computer simulations
title_short	Molecular mechanism of myoglobin autoxidation: Insights from computer simulations
title_full	Molecular mechanism of myoglobin autoxidation: Insights from computer simulations
title_fullStr	Molecular mechanism of myoglobin autoxidation: Insights from computer simulations
title_full_unstemmed	Molecular mechanism of myoglobin autoxidation: Insights from computer simulations
title_sort	molecular mechanism of myoglobin autoxidation: insights from computer simulations
publishDate	2015
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_10895639_v119_n5_p1802_Arcon http://hdl.handle.net/20.500.12110/paper_10895639_v119_n5_p1802_Arcon
work_keys_str_mv	AT rosipabloeduardo molecularmechanismofmyoglobinautoxidationinsightsfromcomputersimulations AT petrukarielalcides molecularmechanismofmyoglobinautoxidationinsightsfromcomputersimulations AT martimarceloadrian molecularmechanismofmyoglobinautoxidationinsightsfromcomputersimulations AT estrindarioariel molecularmechanismofmyoglobinautoxidationinsightsfromcomputersimulations
_version_	1768545661295263744

Molecular mechanism of myoglobin autoxidation: Insights from computer simulations

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