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Crespo, A.; Martí, M.A.; Kalko, S.G.; Morreale, A.; Orozco, M.; Gelpi, J.L.; Luque, F.J.; Estrin, D.A. "Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism" (2005) Journal of the American Chemical Society. 127(12):4433-4444
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Abstract:

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.

Registro:

Documento: Artículo
Título:Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism
Autor:Crespo, A.; Martí, M.A.; Kalko, S.G.; Morreale, A.; Orozco, M.; Gelpi, J.L.; Luque, F.J.; Estrin, D.A.
Filiación:Departamento de Quimica Inorganica, Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires (C1428EHA), Argentina
Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
Dept. de Bioquim. i Biol. Molecular, Facultat de Química, Universitat de Barcelona, Martí i Franqués 1, 08028 Barcelona, Spain
Bioinformatics Unit, IDIBAPS, c/Villaroel 170, 08036 Barcelona, Spain
Palabras clave: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
Año:2005
Volumen:127
Número:12
Página de inicio:4433
Página de fin:4444
DOI: http://dx.doi.org/10.1021/ja0450004
Título revista:Journal of the American Chemical Society
Título revista abreviado:J. Am. Chem. Soc.
ISSN:00027863
CODEN:JACSA
CAS:glycine, 56-40-6, 6000-43-7, 6000-44-8; hemoglobin, 9008-02-0; nitric oxide, 10102-43-9; tyrosine, 16870-43-2, 55520-40-6, 60-18-4; Heme, 14875-96-8; Hemoglobins; Nitric Oxide, 10102-43-9; Oxygen, 7782-44-7
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00027863_v127_n12_p4433_Crespo

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Citas:

---------- APA ----------
Crespo, A., Martí, M.A., Kalko, S.G., Morreale, A., Orozco, M., Gelpi, J.L., Luque, F.J.,..., Estrin, D.A. (2005) . Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism. Journal of the American Chemical Society, 127(12), 4433-4444.
http://dx.doi.org/10.1021/ja0450004
---------- CHICAGO ----------
Crespo, A., Martí, M.A., Kalko, S.G., Morreale, A., Orozco, M., Gelpi, J.L., et al. "Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism" . Journal of the American Chemical Society 127, no. 12 (2005) : 4433-4444.
http://dx.doi.org/10.1021/ja0450004
---------- MLA ----------
Crespo, A., Martí, M.A., Kalko, S.G., Morreale, A., Orozco, M., Gelpi, J.L., et al. "Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism" . Journal of the American Chemical Society, vol. 127, no. 12, 2005, pp. 4433-4444.
http://dx.doi.org/10.1021/ja0450004
---------- VANCOUVER ----------
Crespo, A., Martí, M.A., Kalko, S.G., Morreale, A., Orozco, M., Gelpi, J.L., et al. Theoretical study of the truncated hemoglobin HbN: Exploring the molecular basis of the NO detoxification mechanism. J. Am. Chem. Soc. 2005;127(12):4433-4444.
http://dx.doi.org/10.1021/ja0450004