Biomimetic Reactivity and Spectroscopy of Trinuclear Copper Centers in Multicopper Oxidases

With the support of the Chemistry of Life Processes Program in the Chemistry Division, Dr. Shiyu Zhang from The Ohio State University investigates the mechanism of oxygen reduction reaction at a copper-based enzyme called multicopper oxidase (MCO). Oxygen is essential for life, and many living things use copper enzymes to convert oxygen into water safely and efficiently. This process, called the oxygen reduction reaction (ORR), is important in both biology and energy technologies. However, how exactly MCOs manage this reaction is still not fully understood because of the complex structure of their active site, which contains three copper atoms working together. As many as 25 possible intermediates may form during the oxygen reduction reaction; so far, only four have been clearly identified in the enzyme. Dr. Zhang’s research group will synthesize chemical models that mimic these copper clusters. The models will be used to gain a better understanding of how the ORR works. This pursuit allows graduate students to acquire specialized training in synthetic inorganic chemistry and spectroscopy. This project is also integrated into an outreach program to introduce middle school students in Columbus to scientific research. The research aims to develop a unique cage-like ligand environment for synthetic tricopper clusters, which will be used for the efficient modeling of the multielectron PCET behavior in MCOs. The team will synthesize a series of tricopper(II,II,I) peroxo complexes to model the short-lived peroxy intermediate observed in native proteins. Characterization of the model complexes using spectroscopy will enhance our understanding of the electronic features and reactivity of the natural proteins. Additionally, a tricopper(II,II,II) μ3-O μ2-OH complex will be developed as a model of the native intermediate, shedding light on how proteins regulate the ORR by bifurcating the reduction of the native intermediate into fast and slow catalytic cycles. Kinetic studies of stoichiometric reactions—including electron transfer, proton transfer, and concerted electron-proton transfer—will provide critical insights into how MCOs navigate hundreds of potential PCET pathways to achieve efficient ORR while protecting the protein from oxidative damage. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.