Structural and functional studies will be carried out in order to provide a molecular level of understanding of the role of heme proteins in fundamental physiological processes, including respiration, metabolism, and the regulation of cellular responses. Special emphasis will be placed on the new class of heme sensor proteins. The signal transducers CooA and the H-NOX family of proteins, as well as the heme-regulated enzyme cystathionine beta synthase, have been selected for detailed characterization and dynamical studies of protein conformational change. In addition, the determinants of ligand discrimination by the heme sensors will be studied, with special emphasis on NO selectivity. Resonance Raman spectroscopy will be applied as a structural monitor of the heme group, and of its interaction with the surrounding protein and with exogenous ligands. Dynamical studies will utilize pulse-probe time-resolved resonance Raman spectroscopy on nanosecond and longer time scales. Computation with current DFT and QM/MM techniques will be employed to extract maximum information from the spectra, and to provide insight into the molecular mechanisms of the heme-protein interactions. Heme proteins are critical to human health, and their malfunction is associated with many disease states. Heme proteins ferry oxygen from the lungs to the tissues and then convert oxygen's energy to physiologically useful forms. Other heme proteins are regulators of critical biological processes. Understanding how heme proteins work at the molecular level is an important goal and may lead to new therapies. ? ? ?
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