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Theoretical study of the truncated hemoglobin HbN: exploring the molecular basis of the NO detoxification mechanism

Posted June 8th, 2010 by pschmidtke
TitleTheoretical study of the truncated hemoglobin HbN: exploring the molecular basis of the NO detoxification mechanism
Publication TypeJournal Article
Year of Publication2005
AuthorsCrespo, A, Marti MA, Kalko SG, Morreale A, Orozco M, Gelpi JL, Luque FJ, Estrin DA
JournalJournal of the American Chemical Society
Volume127
Issue12
Pagination4433 - 4444
Date Published2005/03/30/
KeywordsDrug; Models, Heme/chemistry/metabolism; Hemoglobins/chemistry/metabolism; Metabolic Detoxication, Molecular; Mycobacterium tuberculosis/chemistry/metabolism; Nitric Oxide/chemistry/metabolism; Oxidation-Reduction; Oxygen/chemistry/metabolism; Protein Conformation; Quantum Theory; Thermodynamics; Truncated Hemoglobins
AbstractMycobacterium tuberculosis is the causative agent of human tuberculosis. The nitric oxide reaction with oxy-truncated hemoglobin N (trHbN) 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.