Studies on the relationship between the secondary structure of peptide foldamers and their self-assembled morphology

Abstract

The design of self-assembling materials with well-defined 3D shapes from flexible organic molecules presents a significant challenge. Herein we explore the relationship between peptide secondary structure and foldecture morphology in a series of octameric graft foldamers composed of rigid trans-(S,S)-2-aminocyclopentanecarboxylic acid (ACPC) cores to which flexible (L)-$\alpha$-leucine C-terminal moieties are appended. NMR and CD spectroscopy studies indicate that although leucine substitution confers substantial flexibility, the ACPC core templates strong intramolecular hydrogen bonding, making these graft foldamers surprisingly well-structured in solution. Single crystal and powder X-ray crystallography supported by SAED microscopy reveal that leucine substitution leads to both canonical (12-helical) and unusual (12 and 11-, 12, 11 and 10-helical) secondary structures and implicates the branching pattern of intermolecular hydrogen bonds emanating from C-terminal leucine residues in foldecture morphology selection in controlling the 2D to 3D to 1D. Graft foldamers with flexibility sufficient to form 3D hydrogen bonding networks, but rigid enough to remain reasonably well-structured in solution, are optimum substrates for self-assembly. This systematic study develops general rules for shape prediction in self-assembling organic materials derived from flexible organic molecules and enables the development of new materials for unmet challenges.