Enzyme-Inspired Multimetallic Cooperativity: Leveraging Metal Pairing Effects for Heightened Reactivity

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Project Summary Polynuclear mixed-metal active sites enact multielectron transformations central to global ecology. For example, dinitrogen reduction, which is critical for enabling all of life’s biological processes, occurs at an iron-molybdenum cofactor that proves markedly more efficient than its iron-vanadium homolog. Likewise, the oxygen evolving complex of photosystem II features a Ca2+ ion and only maintains oxygen evolution function with Ca and Sr. This specificity is in stark contrast to numerous enzymes that maintain utility when their native metals are substituted for interlopers. These observations raise a critical research question: Why do enzymes select specific metals for specific functions? with the corollary: Why are certain enzymes promiscuous in terms of active site composition? Synthetic model chemistry is perfectly suited to address these queries, as metal substitution in the active site is most often decoupled from perturbations of the protein secondary and tertiary structure that are impossible to emulate abiologically. Using our group’s expertise in preparing multimetallic constructs, the goal of this proposal is to address key questions related to (i) how metal ion identity alters electronic structure in multimetallic active sites, (ii) how well-defined Lewis acid adducts can tune redox potential, pKa, and therefore BDFEs in bimetallic bis(µ-hydroxo) diamond cores, (iii) what is the role of interstitial elements (e.g. O, S, N, P) in tuning the physicochemical properties of multimetallic clusters, and (iv) how proximal metal sites can both cooperatively bind substrates and template stabilizing hydrogen bonds? The viability of these model systems will be established by both spectroscopic comparison to, and reactivity recapitulation of, enzymes of interest (including homobimetallic oxidases, mixed-metal oxidases, and nitric oxide reductase). The systematic connections between model complex structure and function will provide a contextual framework for the development of novel modes of enzyme-inspired reactivity. Exploring oxidant activation proclivity and C–H bond functionalization ability in these systems, sets the stage for the discovery and optimization of new methods in pharmaceutical development, where the requisite reactivity demands the cooperative multipoint binding, efficient redox distribution, and reactive intermediate stabilization that multimetallic architectures can uniquely provide.