Confinement and Catalysis within De Novo Designed Peptide Barrels

De novo protein design has advanced such that many peptide assemblies and protein structures can be generated predictably and quickly. The drive now is to bring functions to these structures, for example, small-molecule binding and catalysis. The formidable challenge of binding and orienting multiple small molecules to direct chemistry is particularly important for paving the way to new functionalities. To address this, here we describe the design, characterization, and application of small-molecule:peptide ternary complexes in aqueous solution. This uses alpha-helical barrel (alpha HB) peptide assemblies, which comprise 5 or more alpha helices arranged around central channels. These channels are solvent accessible, and their internal dimensions and chemistries can be altered predictably. Thus, alpha HBs are analogous to "molecular flasks" made in supramolecular, polymer, and materials chemistry. Using Forster resonance energy transfer as a readout, we demonstrate that specific alpha HBs can accept two different organic dyes, 1,6-diphenyl-1,3,5-hexatriene and Nile red, in close proximity. In addition, two anthracene molecules can be accommodated within an alpha HB to promote anthracene photodimerization. However, not all ternary complexes are productive, either in energy transfer or photodimerization, illustrating the control that can be exerted by judicious choice and design of the alpha HB.