The only known manganese-sequestering biomolecule in mammals, the immune system protein calprotectin, is the first structurally characterized example of a naturally-occurring hexahistidine manganese metal binding site in a metalloprotein. Calprotectin is one of only a handful of manganese- binding metalloproteins which feature an "all-N" (His4 or His6) coordination environment, in contrast to the general propensity of Mn2+-binding sites to contain a mixture of N- and O-donor amino acid ligands. A second example is the cupin protein TM1459, which hosts a His4 manganese site and catalyzes the oxidative cleavage of alkenes. The research proposed here will develop bioinspired functional and structure models of these sites using novel polyimidazole chelating ligands. This work is significant because two important scientific problems will be addressed: the need for selective manganese chelators which would have applications as potential metal-binding therapeutics or as tools for biomedical research, and the need for catalytic methods for oxidative alkene cleavage based on earth-abundant and non-toxic metals. The proposed research is organized into two specific aims: (1) Identify and model the structural and electronic factors responsible for strong Mn2+ binding in calprotectin. Through a combination of synthesis, structural characterization, spectroscopy, binding studies, and computation, novel hexadentate polyimidazole ligands will be used to test bioinspired design principles for selective, high-affinity manganese chelation. These structures will be tested for antibiotic activity against a manganese-dependent pathogen, S. pneumoniae, to determine whether the manganese-dependent adhesion and virulence of this pathogen can be attenuated. (2) Model the polyimidazole-coordinated manganese and iron centers involved in oxidative alkene cleavage. Manganese and iron complexes of imidazole-rich chelating ligands related to those developed in Aim 1 will be applied, optimized, and studied in the context of oxidative double bond cleavage; this bioinspired approach is motivated by the fact that both His4Mn and His4Fe sites in metalloenzymes are competent in this reaction. The contributions from this research are expected to be significant because these systems will provide more faithful biomimetic models of this unusual class of metalloprotein sites with biomedically and technologically important properties. Additionally, by leveraging collaboration between departments and directly involving undergraduate students from Mississippi State University (MSU) in carrying out the proposed work, the research environment at MSU will be enhanced, and highly qualified students will be exposed to bioinorganic chemistry research relevant to NIH's mission.