Abnormalities in protein folding are associated with a growing list of human diseases. Characterization of the origin of these abnormalities at the atomic level is hindered by difficulties in monitoring specific interactions during the folding process. Nuclear magnetic resonance (NMR) spectroscopy is one of the few techniques employed for the study of protein folding that can provide information at the atomic level. Because proteins are very rich in NMR-active protons, the resulting proton-based NMR spectra are rarely fully resolvable. The class of proteins that require cofactors for folding provide an opportunity to study the folding process by monitoring the NMR signal of the cofactor. The proposed work will focus on the use of 199Hg as a probe of metalloprotein folding. Two-dimensional {1H-199Hg} NMR methods will be developed to highlight the biomolecular interactions during the folding process. These studies will also provide a new tool for investigating the pathology of environmental exposure to mercury and certain other metals. X-ray crystallographic methods will be employed to determine the structures of a diverse library of Hg(II) coordination compounds using synthetic ligand models of protein metal-binding sites. This library will extend our knowledge of biologically relevant structure-spectroscopy relationships for 199Hg chemical shifts and coupling constants between 199Hg and 1H in solution and the solid state. Isostructural complexes of other transition metals with favorable NMR properties will be prepared to initiate a systematic comparison of their relative merits as metallobioprobes. Finally, the Hg(II) coordination chemistry of a variety of potentially metal-coordinating cyclic dipeptides will be examined using X-ray crystallography and NMR as a prelude to the application of these new techniques to metalloproteins.
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