Structural dynamics is key to the function of biological macromolecules. Catalytic RNA's, or ribozymes, serve as excellent model systems to study the function of nucleic acids as an essential class of biomolecules. In this project, the hammerhead and delta ribozymes will be studied by a unique array of biochemical and biophysical approaches to answer three fundamental questions: First, how does the RNA strand fold into a three-dimensional structure? Second, how does this structure result in the acquisition of catalytic activity? Third, what role does structural dynamic play in folding and catalysis? Both the hammerhead and the delta ribozyme are well suited to such experiments, since both are small enough for comprehensive studies, yet complex enough that significant conformational changes occur during folding and catalysis. Both model systems catalyze the same chemical reaction, yet are structurally very distinct, suggesting that nature has found two radically different solutions for a common catalytic function.
Specific Aims for both systems are: (1) Map the folding pathway of the ribozyme-substrate complex structurally, kinetically, and thermodynamically; (2) Separate the roles of metal ions in folding and catalysis; (3) Identify and eliminate misfolding pathways. The importance of this work includes advancement of our understanding of the dynamics of RNA structure and how it leads to catalytic activity, and applying this understanding to improving health, through optimizing ribozymes for gene therapy and as biosensors.
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