Covalent Linkage and Macrocylization Preserve and Enhance Synergistic Interactions in Catalytic Amyloids

Abstract

The self‐assembly of short peptides into catalytic amyloid‐like nanomaterials has proven to be a powerful tool in both understanding the evolution of early proteins and identifying new catalysts for practically useful chemical reactions. Here we demonstrate that both parallel and antiparallel arrangements of β‐sheets can accommodate metal ions in catalytically productive coordination environments. Moreover, synergistic relationships, identified in catalytic amyloid mixtures, can be captured in macrocyclic and sheet‐loop‐sheet species, that offer faster rates of assembly and provide more complex asymmetric arrangements of functional groups, thus paving the way for future designs of amyloid‐like catalytic proteins. Our findings show how initial catalytic activity in amyloid assemblies can be propagated and improved in more‐complex molecules, providing another link in a complex evolutionary chain between short, potentially abiotically produced peptides and modern‐day enzymes.