Self-Assembly of Multimolecular Components for Engineering Enzyme-Mimetic Materials

ConspectusNatural enzymes, with their intricate three-dimensional structures, facilitate a wide array of biochemical reactions with exceptional precision and speed. The catalytic capabilities of enzymes arise from the distinctive structures of their active sites, where functional groups collaborate or aid cofactors (organic or ionic) in binding substrates with specificity and catalyzing transformations. Inspired by the structure–function relationship of enzymes, supramolecular self-assembly, a bottom-up approach in nanofabrication, has been employed to create enzyme-mimetic catalysts. However, accurately replicating enzymatic active sites poses a formidable challenge, primarily because of the intricacies in mimicking the complexity of natural protein folding.Many natural biological systems, such as tryptophan synthase or ribosomes, rely on the association of multiple component subunits, each maintaining its structural integrity, to enable efficient and versatile functionalities. The hierarchical self-assembly principles observed in these systems have inspired us to design and self-assemble complementary molecular building blocks that form individual folding or aggregating structures, allowing for precise control over the distribution of reactive groups to create enzyme-like active sites. The customization of either component without disrupting folding structures enables the flexible engineering of catalytic properties. This Account will primarily focus on employing the self-assembly of multiple molecular components, drawing from research progress in our lab, to construct enzyme-mimetic catalysts with built-in metal-dependent or metal-free active sites. The structure–function relationship of these catalysts will be highlighted.To fabricate metal-dependent enzymatic sites, such as heme pockets or copper sites, within the synthetic materials, we create a supramolecular scaffold for stabilizing hemin or forming a copper cluster, followed by the introduction of a second component to enhance substrate adsorption or metal reactivity. The resulting enzyme mimics exhibit remarkable synergistic catalytic activities and possess great stability against the harsh conditions, such as high temperatures, high ionic strength, and cyclic acidification/neutralization treatment. They can be engineered to possess tailorable selectivity toward specific chirality or sizes of substrates and can be externally stimulated to switch between ON/OFF states. These mimics have shown great performances in the sensing of biomolecules of interest, biomass degradation, and aiding in the understanding of the catalytic mechanism of native enzymes. To achieve metal-free catalysis, we introduce a "driving" component to the catalytic component to guide the formation of the assemblies mimicking the activity of hydrolases, photodecarboxylase, or photo-oxidase, with applications in peptide modifications or antibacterial therapy. Moreover, organized components like histidine can catalyze the reactions achieved by heme-dependent enzymes, providing insights into novel biocatalytic mechanisms. Additionally, we discuss the self-assembly of DNAzyme units with DNA nanostructured templates, which provide suitable microenvironments to facilitate the fabrication of the polymer nanopattern with well-defined shapes.In the end, we discuss the key challenges related to structural modeling, enhancing catalytic performance, and increasing the complexity of active sites. We also propose future perspectives for achieving high-value practical applications. Our collective efforts outline strategies for developing robust enzyme-mimetic catalysts, and these general methods may extend to other supramolecular systems aiming to mimic enzymatic catalysis.