Studies on RNA Cleavage: Catalyst Design and Mechanism

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This award by the Inorganic, Bioinorganic and Organometallic Chemistry program supports Professor Janet R. Morrow at the State University of New York at Buffalo to investigate the mechanism of action of a series of mono and dinuclear catalysts of RNA cleavage, which will guide the design of optimal catalysts. The project includes: (1) Characterization of a transition-state analog for phosphodiester cleavage catalyzed by a dinuclear Zn(II) complex to test the hypothesis that the large catalytic effect for these catalyzed reactions results from selectivity in binding of the dianionic reaction transition state at a densely charged cationic catalytic core. (2) Determination of the solvent deuterium isotope effect over a broad range of pH for cleavage of a dinucleoside substrate catalyzed by the dinuclear Zn(II) complex, which will show whether the catalyzed reaction proceeds through a formal proton transfer from an acidic site at the catalyst to the leaving group. (3) The synthesis of new catalysts that incorporate the following design elements. (a) Specificity for binding of nucleosides involving new dinuclear catalysts in which one Zn(II) macrocycle provides binding specificity for a uridine-nucleoside and a second Zn(II)- or Ln(III)- macrocycle acts as the active catalyst of phosphodiester cleavage. (b) Maximization of charge density at a catalytic core of a dinuclear catalyst using a dinuclear Zn(II) complex utilizing a linker alkoxide group that acts to draw the Zn(II) cations together at a catalytic core. The projects on catalysis by lanthanide ions will utilize the new laser facility for lanthanide (Ln) luminescence research at the University of Buffalo (UB), which was established with support from the NSF-MRI program and is expected to foster synergistic interactions and the exchange of ideas. The laser system will also have a positive impact on the training of undergraduate and graduate students at UB, outside graduate universities and at four-year colleges. Experiments that focus on Eu(III) luminescence will be developed and added to the undergraduate curriculum at UB. Interactions are planned with educators at Hunter College, the University of Iowa and Skidmore College that will involve underrepresented minority students from these universities and colleges in projects that utilize this laser.