Enzyme-inspired multimetallic cooperativity: leveraging metal pairing effects for heightened reactivity

The University of Michigan received a $2.01 million Project Grant from the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859), awarded September 1, 2025, with completion targeted for August 31, 2029. This four-year research initiative focuses on enzyme-inspired multimetallic cooperativity and the design of synthetic model systems that investigate how metal ion identity and pairing effects influence catalytic reactivity in biological systems. The research specifically addresses fundamental questions regarding metal selection specificity in polynuclear active sites and aims to elucidate the mechanisms by which multimetallic clusters achieve multielectron transformations central to critical biological processes such as dinitrogen reduction and oxygen evolution.

The primary research deliverables include development and spectroscopic characterization of well-defined bimetallic and multimetallic model compounds, mechanistic investigations into how metal substitution alters electronic structure and redox properties, and demonstration of synthetic systems that recapitulate the reactivity profiles of target enzymes including homobimetallic oxidases, mixed-metal oxidases, and nitric oxide reductase. The research will employ Lewis acid-base chemistry and interstitial element tuning to manipulate binding affinity and substrate cooperativity, with comparative validation against natural enzyme systems. These outputs are designed to advance fundamental understanding of bioinorganic chemistry and may inform the rational design of synthetic catalysts for applications in energy conversion and chemical transformation.

Abstract

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.