Covalent linkage and macrocylization preserve and enhance synergistic interactions in catalytic amyloids

Self-assembly of short peptides into catalytic amyloid-like nanomaterials has proven to be a powerful tool in both understanding 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 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.