In crystallo biomimetic oxygenase chemistry within peptidic frameworks - title: in crystallo biomimetic oxygenase chemistry within peptidic frameworks abstract: mononuclear non-heme FE and CU sites in…

In crystallo biomimetic oxygenase chemistry within peptidic frameworks - title: in crystallo biomimetic oxygenase chemistry within peptidic frameworks abstract: mononuclear non-heme FE and CU sites in oxygenases functionalize the highly inert c-h bonds of substrates involved in metabolism, natural product synthesis, and global biogeochemical cycles, all of which directly impact human health. Despite the importance of these enzymes, the structures and properties of many key enzymatic intermediates are not fully understood. Synthetic analogs of the intermediates facilitate more in-depth studies, but current models have shown that the protein environment, or lack thereof, significantly affects reactivity. Site-isolation, weak-field ligands, and noncovalent secondary interactions are hallmarks of oxygenase active sites, but these features are difficult to simultaneously replicate in synthetic systems. To address these gaps, our laboratory has developed single-crystalline peptide assemblies (or "frameworks") that bind metals in their porous channels using amino acid residues. Our central hypothesis is that usage of peptide-based coordinating groups allows direct comparisons between the model system and the enzyme, while the crystalline matrix stabilizes reactive species for structure determination by x-RAY crystallography. We have reproduced the critical facial triad coordination (2HIS/1-carboxylate) for non-heme FE sites, from which we will explore the structures and chemistry of the fleeting high-valent intermediates relevant to the enzyme mechanism. The CU versions of these frameworks are also appropriate models for the active site of particulate methane monooxygenase (pmmo), whose active site has been long-debated and recently postulated to be a single CU site bound to a 2HIS/ASP ligand set. Given the modularity and ease of peptide synthesis, we will tune the structures of these sites to obtain detailed structure-function correlations that will illuminate how protein environments elicit remarkable inorganic reactivity. The outcomes of this research are expected to fill in key gaps in the mechanism of these enzymes and inform the design of mechanism-based therapeutics, as well as catalysts for pharmaceutical synthesis, water remediation, and mitigation of climate change.