Professor Benner will lead a project that combines organic synthesis, biological chemistry, in vitro evolution (lVE) and univariate statistical analysis that will develop the physical organic chemical tools needed to quantitate the impact of adding chemical functionality (amino, thiol, imidazole, peptides, and metal chelating groups) via covalent attachment to catalytic DNA molecules. This work will first address the paradox that arises from the observation that endowing DNA and RNA libraries with additional functionality evidently improves the catalytic potential of nucleic acids by only a factor of two to ten, not by the orders of magnitude expected from standard Structure Theory in Organic Chemistry. A set of five hypotheses that account for the orders-of-magnitude discrepancy between expectation and observation will be tested, including models that hold (a) that our view of the role of functionality in catalysis is naive, (b) that the functional endowment of natural DNA (phosphates and hydrogen bond donating and accepting groups) are sufficient for catalysis in general, (c) that the functionality recruited non-covalently by nucleic acids from solution (in particular, divalent cations such as Mg++) overwhelms the contribution of covalently linked functionality, (d) that lVE experiments lose the best catalysts, and (e) that more than one type of functional group is needed before the expected large benefit from functionality is seen. This will require careful assessment of the kinetic order of the reaction being effected by the selected DNA molecules (first order, unimolecular, with the catalytic step rate determining?).
With this Award, the Organic and Macromolecular Chemistry Program (OMC) and the Molecular Biochemistry Program in the Division of Molecular and Cellular Biosciences (MCB) will support the research of Professor Steven A. Benner of the University of Florida. Professor Benner's work is expected to have broad impact. From a practical perspective, we may learn how to truly get "catalysis on demand" from IVE experiments, useful for everything from biomedicine to environmental remediation. From a scientific perspective, we will understand in greater depth the possibilities of single biopolymer systems playing a role in the origin of life. From a methodological perspective, he will develop tools that permit IVE to explore the distribution of chemical properties in "structure space" defined by a DNA sequence. And, from a theoretical perspective, the work may end up altering, perhaps dramatically, our global view of the relationship between functionality and reactivity in nucleic acids.
