Exploring the self-assembly of β-peptide foldamers: Modulation of hydrophilicity and hydrophobicity

Abstract

In nature, most organisms utilize molecular self-assembly to form supramolecular architectures that perform vital functions. The morphology of supramolecular architectures is closely related to their function. However, understanding and mimicking these morphologies still remains a challenge due to the complexity of the structures with the flexibility and dynamics of natural building blocks. β-peptide foldamers composed of cyclic β-amino acids exhibit rigid and well-organized secondary structures not found in nature due to intramolecular interactions induced by ring constraints of unnatural amino acids. Among these, a β-peptide foldamer ($ACPC_6$) composed of six trans-2-aminocyclopentane-1-carboxylic acids (trans-ACPC) exhibits high modularity with a rigid 12-helix and lateral hydrophobic area. Self-assembly of these peptides forms foldecture (foldamer+ architecture), which are three-dimensional supramolecular architectures that exhibit a unique shape. In this thesis, we explored the effects of hydrophilicity and hydrophobicity on the self-assembly through the self-assembled architecture of highly modular β-peptides. For this purpose, we used $ACPC_6$ as a standard backbone to introduce hydrophilic and hydrophobic functional groups. The self-assembled architecture of foldamers introduced with hydrophilic ethylene glycol exhibited two-dimensional growth, and co-assembly with $ACPC_6$ realized directional growth control by hydrophilicity modulation. Furthermore, the foldamers introduced with hydrophobic difluoromethylene realized the various morphologies of foldectures due to hydrophobicity modulation depending on the position and number of introduced fluorine atoms. Our findings will provide guidance for the understanding of self-assembly to form supramolecular architectures and the rational design of directional biomimetic materials.