RNAs play crucial roles in cellular metabolic processes, e.g. ribozymes in RNA-processing or riboswitches in the regulation of protein expression. Metal ions thereby guide and determine folding and function of every complex nucleic acid structure. Recently, it has become increasingly evident that RNA folding and catalysis are extremely sensitive to changes in concentration and nature of the metal ion involved as well as to single-atom changes in metal ion complexes. The elucidation of the specific binding of certain metal ions and their complexes by nucleic acids poses an enormous challenge. This recognition process must depend solely on basic coordination chemical principles but is poorly understood. The goal of this project is to understand the effect of metal ions and their complexes on local and global structure formation of single large RNAs: Specifically, the influence of metal ions on the assembly of the catalytic core of group II intron ribozymes as well as the influence of single corrin side chains of coenzyme B12 to induce the structural change of its 202 nucleotide long riboswitch will be characterized. Combining classical Inorganic, Coordination, Analytical, and Organic Chemistry with Biophysics, we will apply single molecule Förster Resonance Energy Transfer spectroscopy (smFRET) together with hydrolytic cleavage experiments and chemical synthesis. SmFRET studies allow us to investigate every molecule individually instead of a bulk signal and thus to observe also minor populations. Our results will reveal how single metal ions and ligand atoms guide and influence global structure, folding, and function of ribozymes and riboswitches, and promise to have a significant impact on Biological Inorganic Chemistry, RNA Biochemistry, as well as Medicinal Chemistry.
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