conferencia invitada: Computer simulation of ligand binding and migration in globins

M.A. MARTI; A. CRESPO; L. CAPECE; L. BOECHI; D.A. ESTRIN

Napoles, Italia

Conferencia; XV Internacional Conference on Dioxygen Binding and Sensing Proteins; 2006

We present an investigation of the molecular basis of the modulation of ligand binding in globins using computer simulation. Hybrid quantum-classical (QM-MM) calculations are applied to explore distal 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 highlighting the virtues and the limitations of the applied methodologies. These examples cover a wide range of O2-affinities, and include: the truncated-N hemoglobin from Mycobacterium Tuberculosis, the mammalian muscular O2 storage protein myoglobin, the hemoglobin from the parasitic nematode Ascaris lumbricoides, the oxygen transporter in the root of leguminous plants Leghemoglobin, 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 techniques in combination with advanced sampling tools. These techniques yield significant information about 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. The QM-MM and the classical simulation tools, by covering different time and space scales, complement each other in providing a complete picture of the mechanism of ligand binding to globins.