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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todo:paper_10895639_v119_n5_p1802_Arcon2023-10-03T16:04:50Z Molecular mechanism of myoglobin autoxidation: Insights from computer simulations Arcon, J.P. Rosi, P. Petruk, A.A. Marti, M.A. Estrin, D.A. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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 Arcon, J.P. Rosi, P. Petruk, A.A. Marti, M.A. Estrin, D.A. 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. |
| format |
JOUR |
| author |
Arcon, J.P. Rosi, P. Petruk, A.A. Marti, M.A. Estrin, D.A. |
| author_facet |
Arcon, J.P. Rosi, P. Petruk, A.A. Marti, M.A. Estrin, D.A. |
| author_sort |
Arcon, J.P. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_10895639_v119_n5_p1802_Arcon |
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| _version_ |
1807317071852208128 |