Computer simulation of chemical reactivity of globins

D.A. ESTRIN

Venecia, Italia

Workshop; XII School of Biophysics (Italian Biophysical Society) The ever changing world of globins; 2008

Italian Biophysical Society

Computer simulation of chemical reactivity of globinsDarío A. EstrinDepartamento de Quımica Inorganica,Analitica y Quımica Fısica/INQUIMAE-CONICET,Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos Aires, Buenos Aires, ArgentinaWe present an investigation of the molecular basis of chemical reactivity modulation in globins using computer simulation. Hybrid quantum-classical (QM-MM) calculations are applied to exploredistal and proximal effects on ligand binding to the heme. Trends in binding energies and in the kinetic constants are illustrated through a number of selected examples including the truncated-Nhemoglobin from Mycobacterium Tuberculosis, mammalian myoglobin, the hemoglobin from the parasitic nematode Ascaris lumbricoides, the oxygen transporter in the root of leguminous plantsLeghemoglobin, and the Cerebratulus lacteus nerve tissue hemoglobin.We present also an investigation of the interplay between ligand migration and protein dynamics obtained through classical molecular dynamics (MD) techniques in combination with advancedsampling tools. These techniques yield significant information about free energy profiles and possible secondary docking sites. Results for the deoxy and oxy truncated N hemoglobin ofMycobacterium 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 tothe 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 bridgepromotes the stabilization of the pentacoordinated species, thus favoring the reactive state and suggesting a O2 storage function for neuroglobin.