ESTRIN Dario Ariel
congresos y reuniones científicas
Exploring Structure, Dynamics, and Chemical Reactivity of Heme Proteins using Computer Simulation
Conferencia; VII Iberoamerican Congress of Biophysics; 2000
Institución organizadora:
Sociedad Iberoamericana de Biofisica
<!-- @page { size: 21cm 29.7cm; margin: 2cm } P { margin-bottom: 0.21cm } --> We present an investigation of the molecular basis of chemical reactivity modulation in heme proteins using computer simulation. Hybrid quantum-classical (QM-MM) calculations are applied to explore distal and proximal effects on oxygen binding to the heme. Trends in binding energies and in the kinetic constants are illustrated through a number of selected examples, including the truncated-N hemoglobin from Mycobacterium Tuberculosis, mammalian myoglobin, the hemoglobin from the parasitic nematode Ascaris lumbricoides, the oxygen transporter in the root of leguminous plants Leghemoglobin, the Cerebratulus lacteus nerve tissue hemoglobin and Archea protoglobin. In addition, we also present a QM-MM investigation of the oxygen attack to the substrate mechanism in tryptophane and indoleamine dioxygenases, two related heme proteins of physiological relevance. We present also an investigation of the interplay between ligand migration and protein dynamics obtained through classical molecular dynamics (MD) techniques in combination with advanced sampling tools. These techniques yield significant information about migration free energy profiles and possible secondary docking sites. Results for the deoxy and oxy truncated N hemoglobin of Mycobacterium Tuberculosis, presented as an illustrative example, suggest that the truncated hemoglobin N has evolved a dual-path mechanism for selective/distinct migration of O2 and NO to the heme, to achieve efficient NO detoxification. Finally, we present also an analysis of the molecular basis of hexacoordination in human neuroglobin, which show that protein oxidation through the formation of a disulfide bridge promotes the stabilization of the pentacoordinated species, thus favoring the reactive state and suggesting a O2 storage function for neuroglobin. Results obtained using high pressure simulations of neuroglobin and myoglobin suggest that the equilibrium between the 5c and the 6c states in globins is largely controlled by the structure and dynamics of the CD region.