Porous Framework Assembly Creates Functional Tertiary Folds in Small Peptides

Abstract

There is significant interest in recreating the protein tertiary structure in simpler systems, which can enable the precise and modular organization of multiple functional groups for enhancing molecular recognition and catalysis. Small peptides are minimalist analogs of proteins; however, their limited size highly disfavors folding into tertiary structures, especially those that also possess open binding sites needed for function. Here, we report that 3-dimensional self-assembly into a porous crystalline framework overcomes this limitation, producing modular tertiary structures in peptides shorter than 20 amino acids with tunable binding sites. As shown by X-ray crystallography, this framework-mediated folding tolerates many sequences with a broad range of functional groups, and it generates precise confined environments that are dynamic and mutationally robust. Thus, these pores can be programmed to selectively bind complex molecular guests such as nucleotides and perfluoroalkyl substances through the cooperative engagement of up to 10 distinct residues. These results demonstrate that a well-defined tertiary structure can exist in very short peptides and can impart tunable protein-like function to synthetic porous materials.