Perturbation of Nucleotide Acidity in RNA Folding and Catalysis

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With the support of the Organic and Macromolecular Chemistry Program, Professor Scott A. Strobel, of the Department of Molecular Biophysics and Biochemistry at Yale University, is undertaking a combinatorial approach to the exploration of acidity perturbations important for RNA structure and function. By exploiting the technique of Nucleotide Analog Interference Mapping, Professor Strobel simultaneously yet individually monitors the effect of incorporating a nucleotide analog at every position within an RNA molecule. After developing a set of nucleotide analogs which retain a full set of base functional groups, but which have altered acidity of the A- and C-imino groups, a variety of RNAs will be screened for functionally important protonation sites. These analogs will then be brought to bear on an investigation of potential base ionization events important for the catalytic activity of three self-processing ribozymes, specifically the hepatitis delta virus, the Varkud Satellite, and hairpin RNA enzymes.Many biochemical reactions are facilitated by "general" acid and/or base catalysis, wherein the reaction is assisted by a partial proton transfer somewhere along the reaction pathway. Since they possess acidic and basic groups of the appropriate strength, protein enzymes are well-suited to catalyze such reactions. Like proteins, large ribonucleic acid (RNA) molecules can also adopt complex structures and catalyze chemical reactions. However, unlike the protein enzymes, RNA does not contain acidic or basic groups which would be expected to participate in general acid or base catalysis. This implies that in particular circumstances, the acidity of a group within RNA must be substantially shifted by its specific, local microenvironment within the RNA molecule. With the support of the Organic and Macromolecular Chemistry Program, Professor Scott A. Strobel, of the Department of Molecular Biophysics and Biochemistry at Yale University, has developed a technique permitting the rapid analysis of the effects of multiple changes on the structure and properties of RNA. By developing a new set of "tools" for the application of this technique to the analysis of acidity effects, Professor Strobel will elucidate the molecular underpinnings of general acid and base catalysis by RNA, providing information about RNA structure and function and suggesting new ways to think about molecular evolution and catalysis.