A minimalistic hydrolase based on co-assembled cyclic dipeptides.

The self-assembly of small peptides into larger aggregates is an important process for the fundamental understanding of abiogenesis. In this article we demonstrate that blends of cyclic dipeptides (2,5-diketopiperazines - DKPs) bearing either histidine or cysteine in combination with a lipophilic amino acid form highly stable aggregates in aqueous solution with esterase-like activity. We demonstrate that the catalytic activity is based on an intermolecular cooperative behavior between histidine and cysteine. A high control of the molecular arrangement of the peptide assemblies was gained by C-H-π interactions between Phe and Leu or Val sidechains, resulting in a significant increase in catalytic activity. These interactions were strongly supported by Hartree-Fock calculations and finally confirmed via1H-NMR HRMAS NOE spectroscopy.