Editing Enzymes with Multiscale Metal-Based Components

Enzymes are powerful natural catalysts distinguished by high efficiency and selectivity. The use of enzymes in the chemical industry can theoretically enable numerous efficient and sustainable reaction pathways. Nevertheless, the application of enzymes is hindered by their narrow catalytic repertoire. Enzymes are readily deactivated under nonnatural environments, and their reaction types are limited. Developing enzymes with new catalytic functions has been a longstanding challenge in the field of biocatalysis. Strategies such as directed evolution and de novo protein design have been very successful in designing new enzymes. However, as both approaches rely on the engineering of amino acid sequences of proteins, they remain constrained and cannot fully meet the growing demand for non-natural biocatalysis. Incorporating abiotic components with enzymes is a powerful tool for editing enzymes to render new catalytic capabilities. Metal-based components possess a broad catalytic repertoire, structural stability, and multifunctionality, making them promising building blocks for enzyme editing. This Account summarizes our contributions over the past decade in editing enzyme catalysts with metal-based components as a scale-dependent evolution, from nanoscale environmental modulation to atom-scale active site redefinition, illustrating how enzyme editing with metal-based components can systematically address non-natural catalytic challenges. A conceptual framework in which enzymes are edited with metal-based components across scales from the nanometer to the atomic dimension is introduced, establishing a logical basis for integrating biocatalysis with abiotic reactivity. At the nanoscale, enzymes are encapsulated in metal-based frameworks to improve the configuration stability, enabling catalysis under non-native and harsh conditions. The robustness of enzymes under extreme pH, high temperature, and organic solvent can be largely enhanced through the regulation of metal-based frameworks. At the sub-nanoscale, metal clusters are embedded within enzyme scaffolds to construct enzyme-metal hybrid catalysts. By integration of enzymatic and chemical catalysis, new non-natural catalytic processes can be established. At the atomic scale, metal atoms are incorporated into the enzyme catalytic pocket, creating new hybrid active sites. The hybrid active site endows an enzyme with capabilities to drive new-to-nature reactions, unlocking an expanded enzyme catalytic space. This work provides a unifying conceptual framework that clarifies how metal-based components can be strategically employed to reprogram enzyme stability, functionality, and reactivity. We hope that the strategies and concepts discussed herein offer comprehensive design principles for biohybrid catalysts and establish a foundation for reprogramming enzymatic function beyond evolutionary limitations.