The role of aromatic residues in controlling the supramolecular chirality of short amphiphilic peptides

Although the relationship between molecular and supramolecular chirality remains elusive, the existing results have demonstrated the vital role of hydrophilic motifs in controlling the supramolecular handedness of peptide nanofibrils compared with hydrophobic ones. However, unlike conventional hydrophobic residues, we speculate that aromatic hydrophobic residues are mostly likely to play a unique role in regulating the supramolecular handedness because the π−π stacking interactions of their side chains are directional like hydrogen bonding and can direct high levels of self-assembly due to the geometric confining of aromatic rings. To confirm this hypothesis, we here design a series of amphiphilic short peptides, with their hydrophobic motifs being composed of aromatic residues. Their short lengths not only favor their structural stability, synthesis, and sequence variation but also enable us to readily link their molecular and supramolecular structures. Through the combination of experiments and theoretical simulations, we demonstrate that the peptides containing L-form aromatic residues form left-handed nanofibrils while those containing D-form aromatic residues assemble into right-handed ones, irrespective of the chirality of their C-terminal hydrophilic residue. Theoretical calculations revealed that the stacking of aromatic side chains between β-strands directed the twisting direction of the β-sheets formed, with L- and D-form phenylalanine side chains stacking in a clockwise and anti-clockwise way, and more ordered and stronger aromatic stacking for homochiral peptides facilitated the formation of nanofibrils with a marked tubular feature. This study has bridged the knowledge gap in our understanding of how aromatic residues affect the supramolecular chirality of short peptides.