The Chemistry of Life Sciences Program funds Professor Olof Einarsdottirof the University of California-Santa Cruz for research entitled "Protein Tuning of Metal Centers and Ligand Pathways to Achieve Specific Enzymatic Functions." The goal of this research is to understand how metal centers that bind O2, NO, and CO are tuned by the protein environment within cells in order to perform specific catalytic functions. Heme-copper oxidases from three oxidase families, A, B and C will be investigated. The approach involves novel photolabile O2 and NO carriers, single and double-laser techniques and classical/quantum mechanical calculations to accomplish two goals. The first goal is to determine the structural and dynamic features of the protein environment that give rise to mechanistic differences in the O2 and NO reduction in the heme-copper oxidases. The functional roles of specific residues, as well as the constriction points and docking sites that control ligand accessibility to and from the active site, will be established. A second goal is to determine how a diatomic ligand that is bound to the binuclear center or in a binding pocket of the Thermus thermophilus ba3, E. coli bo3, aa3, and cbb3 oxidases affects the binding of a second ligand. The proposed experiments will establish how the protein environment can tune metal-based prosthetic group(s) and ligand pathways to modulate catalytic functions of the metal centers in the heme-copper oxidases for different physiological environments. The proposed research will also provide excellent research opportunities for graduate and undergraduate students.

Metal atoms like iron and copper form complexes with certain proteins in cells and play essential roles in important functions such as respiration, in which oxygen is used to generate energy, and photosynthesis. To carry out these functions, the chemical properties of the metals are altered by the surrounding protein environment. This research will advance knowledge of how the protein environment modulates access of small ligands, such as oxygen (O2), to the metal centers in different heme-copper oxidases so that these enzymes can carry out the essential function of generating energy in different physiological environments. Special chemicals are used that can bind O2 and other gases, such as nitric oxide (NO), then instantly release them with a flash of laser light. These reactions can be monitored on time scales as fast as ten-billionths of a second. Calculations are used to simulate the movement of O2 and NO to the metal centers. The combination of experiments and simulations offers a unique approach to evaluate proposed mechanisms for ligand binding to metal centers, as well as to provide excellent research opportunities for both graduate and undergraduate students. This project is receiving co-funding from the Biomolecular Dynamics, Structure and Function Cluster in the Division of Molecular and Cellular Biosciences.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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David Rockcliffe
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University of California Santa Cruz
Santa Cruz
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