Chiral inversion induced by aromatic interactions in short peptide assembly

Although hydrophobic interactions provide the main driving force for initial peptide aggregation, their role in regulating suprastructure handedness of higher-order architectures remains largely unknown. We here interrogate the effects of hydrophobic amino acids on handedness at various assembly stages of peptide amphiphiles. Our studies reveal that relative to aliphatic side chains, aromatic side chains set the twisting directions of single beta-strands due to their strong steric repulsion to the backbone, and upon packing into multi-stranded beta-sheets, the side-chain aromatic interactions between strands form the aromatic ladders with a directional preference. This ordering not only leads to parallel beta-sheet arrangements but also induces the chiral flipping over of single beta-strands within a beta-sheet. In contrast, the lack of orientational hydrophobic interactions in the assembly of aliphatic peptides implies no chiral inversion upon packing into beta-sheets. This study opens an avenue to harness peptide aggregates with targeted handedness via aromatic side-chain interactions. The role of hydrophobic interactions in the regulation of the handedness of peptide superstructures is unknown. Here, the authors show that aromatic side chains set the twisting directions of the single beta-strands of peptide amphiphiles.