This Small Grant for Exploratory Research is supported by the Inogranic, Bioinorganic, and Organometallic Chemistry Program for development of a novel synthetic route to functional metalloproteins. Dr. John Caradonna of the Department of Chemistry, Yale University, will use a combinatorial approach to construct proteins with active metal sites inside host proteins of known structure. Effectively, reaction initiates a search for the constellation of backbone positions that satisfies the geometry of the active site without affecting the host protein's tertiary structure. The mutant proteins constructed would be tested for enzymatic activity. The initial experiments will attempt to synthesize the iron site of superoxide dismutase, so a successful outcome could lead to a powerful tool in reducing tissue damage resulting from superoxide. One immediate result will be the ability to test the effect of secondary protein topologies on the chemistry of metalloproteins. The active sites of metal-containing enzymes consist of metals bound to proteins folded in a certain pattern. By devising a means of adding the metal without disrupting the folding pattern, this research could lead to a method of synthesizing metalloenzymes that are functional, and thus ready for use in biological investigations and applications. In the process, the effect of protein structure on activity of metalloenzymes will be studied.
