Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism
Mycobacterium tuberculosis is the causative agent of human tuberculosis. The nitric oxide reaction with oxy-truncated hemoglobin N (IrHbN) has been proposed to be responsible for the resistance mechanism by which this microorganism can evade the toxic effects of NO. In this work, we explore the mole...
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2005
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paper:paper_00027863_v127_n12_p4433_Crespo2023-06-08T14:22:40Z Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism Crespo, Alejandro Martí, Marcelo Adrián Kalko, Susana G. Estrin, Dario Ariel Bacteria Computer simulation Diffusion Diseases Microorganisms Proteins Quantum theory Reaction kinetics Toxicity Detoxifications Mycobacterium tuberculosis Nitric oxides Toxic effects Nitrogen compounds glycine hemoglobin ligand nitric oxide tyrosine article bacterial infection binding site cell survival detoxification enzyme active site gene rearrangement molecular dynamics Mycobacterium tuberculosis quantum theory simulation tuberculosis Heme Hemoglobins Metabolic Detoxication, Drug Models, Molecular Mycobacterium tuberculosis Nitric Oxide Oxidation-Reduction Oxygen Protein Conformation Quantum Theory Thermodynamics Mycobacterium tuberculosis is the causative agent of human tuberculosis. The nitric oxide reaction with oxy-truncated hemoglobin N (IrHbN) has been proposed to be responsible for the resistance mechanism by which this microorganism can evade the toxic effects of NO. In this work, we explore the molecular basis of the NO detoxification mechanism using a combination of classical and hybrid quantum-classical (QM-MM) simulation techniques. We have investigated the structural flexibility of the protein, the ligand affinity properties, and the nitric oxide reaction with coordinated O2. The analysis of the classical MD trajectory allowed us to identify Phe62 as the gate of the main channel for ligand diffusion to the active site. Moreover, the opening of the channel stems from the interplay between collective backbone motions and local rearrangements in the side chains of the residues that form the bottleneck of the tunnel. Even though the protein environment is not found to make a significant contribution to the heme moiety catalyzed reaction, the binding site influences the physiological function of the enzyme at three different levels. First, by isolating the intermediates formed in the reaction, it prevents nondesired reactions from proceeding. Second, it modulates the ligand (O2, NO) affinity of the protein, which can be ascribed to both distal and proximal effects. Finally, the stabilization of the Tyr33-Gln58 pair upon O2 binding might alter the essential dynamics of the protein, leading in turn to a mechanism for ligand-induced regulation. © 2005 American Chemical Society. Fil:Crespo, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Martí, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Kalko, S.G. 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. 2005 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v127_n12_p4433_Crespo http://hdl.handle.net/20.500.12110/paper_00027863_v127_n12_p4433_Crespo |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
Bacteria Computer simulation Diffusion Diseases Microorganisms Proteins Quantum theory Reaction kinetics Toxicity Detoxifications Mycobacterium tuberculosis Nitric oxides Toxic effects Nitrogen compounds glycine hemoglobin ligand nitric oxide tyrosine article bacterial infection binding site cell survival detoxification enzyme active site gene rearrangement molecular dynamics Mycobacterium tuberculosis quantum theory simulation tuberculosis Heme Hemoglobins Metabolic Detoxication, Drug Models, Molecular Mycobacterium tuberculosis Nitric Oxide Oxidation-Reduction Oxygen Protein Conformation Quantum Theory Thermodynamics |
| spellingShingle |
Bacteria Computer simulation Diffusion Diseases Microorganisms Proteins Quantum theory Reaction kinetics Toxicity Detoxifications Mycobacterium tuberculosis Nitric oxides Toxic effects Nitrogen compounds glycine hemoglobin ligand nitric oxide tyrosine article bacterial infection binding site cell survival detoxification enzyme active site gene rearrangement molecular dynamics Mycobacterium tuberculosis quantum theory simulation tuberculosis Heme Hemoglobins Metabolic Detoxication, Drug Models, Molecular Mycobacterium tuberculosis Nitric Oxide Oxidation-Reduction Oxygen Protein Conformation Quantum Theory Thermodynamics Crespo, Alejandro Martí, Marcelo Adrián Kalko, Susana G. Estrin, Dario Ariel Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism |
| topic_facet |
Bacteria Computer simulation Diffusion Diseases Microorganisms Proteins Quantum theory Reaction kinetics Toxicity Detoxifications Mycobacterium tuberculosis Nitric oxides Toxic effects Nitrogen compounds glycine hemoglobin ligand nitric oxide tyrosine article bacterial infection binding site cell survival detoxification enzyme active site gene rearrangement molecular dynamics Mycobacterium tuberculosis quantum theory simulation tuberculosis Heme Hemoglobins Metabolic Detoxication, Drug Models, Molecular Mycobacterium tuberculosis Nitric Oxide Oxidation-Reduction Oxygen Protein Conformation Quantum Theory Thermodynamics |
| description |
Mycobacterium tuberculosis is the causative agent of human tuberculosis. The nitric oxide reaction with oxy-truncated hemoglobin N (IrHbN) has been proposed to be responsible for the resistance mechanism by which this microorganism can evade the toxic effects of NO. In this work, we explore the molecular basis of the NO detoxification mechanism using a combination of classical and hybrid quantum-classical (QM-MM) simulation techniques. We have investigated the structural flexibility of the protein, the ligand affinity properties, and the nitric oxide reaction with coordinated O2. The analysis of the classical MD trajectory allowed us to identify Phe62 as the gate of the main channel for ligand diffusion to the active site. Moreover, the opening of the channel stems from the interplay between collective backbone motions and local rearrangements in the side chains of the residues that form the bottleneck of the tunnel. Even though the protein environment is not found to make a significant contribution to the heme moiety catalyzed reaction, the binding site influences the physiological function of the enzyme at three different levels. First, by isolating the intermediates formed in the reaction, it prevents nondesired reactions from proceeding. Second, it modulates the ligand (O2, NO) affinity of the protein, which can be ascribed to both distal and proximal effects. Finally, the stabilization of the Tyr33-Gln58 pair upon O2 binding might alter the essential dynamics of the protein, leading in turn to a mechanism for ligand-induced regulation. © 2005 American Chemical Society. |
| author |
Crespo, Alejandro Martí, Marcelo Adrián Kalko, Susana G. Estrin, Dario Ariel |
| author_facet |
Crespo, Alejandro Martí, Marcelo Adrián Kalko, Susana G. Estrin, Dario Ariel |
| author_sort |
Crespo, Alejandro |
| title |
Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism |
| title_short |
Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism |
| title_full |
Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism |
| title_fullStr |
Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism |
| title_full_unstemmed |
Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism |
| title_sort |
theoretical study of the truncated hemoglobin hbn: exploring the molecular basis of the no detoxification mechanism |
| publishDate |
2005 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v127_n12_p4433_Crespo http://hdl.handle.net/20.500.12110/paper_00027863_v127_n12_p4433_Crespo |
| work_keys_str_mv |
AT crespoalejandro theoreticalstudyofthetruncatedhemoglobinhbnexploringthemolecularbasisofthenodetoxificationmechanism AT martimarceloadrian theoreticalstudyofthetruncatedhemoglobinhbnexploringthemolecularbasisofthenodetoxificationmechanism AT kalkosusanag theoreticalstudyofthetruncatedhemoglobinhbnexploringthemolecularbasisofthenodetoxificationmechanism AT estrindarioariel theoreticalstudyofthetruncatedhemoglobinhbnexploringthemolecularbasisofthenodetoxificationmechanism |
| _version_ |
1768544937185378304 |