Betaine‐Conjugated ß‐Peptide Foldamers: Influence of Quaternary Charge on Self‐Organization and MorphologyFormation

The modification of well‐known β ‐peptide helices has been achieved by the application of N‐terminal betaine conjugation. The 3D self‐organization of oligomers formed by [1 S ,2 S ]‐2‐aminocyclopentanecarboxylic acid (ACPC), [1 R ,2 R ]‐2‐aminocyclohexanecarboxylic acid (ACHC), and an alternating heterochiral homooligomer of [1 S ,2 S ]‐ACPC and [1 R ,2 R ]‐ACPC was studied. Results of NMR, ECD, FT‐IR, and molecular modeling showed that for [1 S ,2 S ]‐ACPC pentamer ( 1 ), the betaine conjugation did not affect the folding to an H12 helix. In contrast, for the [1 R ,2 R ]‐ACHC tetramer ( 2 ) betaine conjugation notably influenced the folding, and an H14 helix was observed instead of the expected H10 helix. In addition, this is the first observation of self‐association for an H12 helix forming β ‐peptide. Based on TEM images, this association leads to vesicle morphologies. For the alternating heterochiral homooligomer [1 S ,2 S ]‐ACPC and the [1 R ,2 R ]‐ACPC pentamer ( 3 ), betaine conjugation enhances the solubility of the system. Moreover, the formation of an expected E‐strand can be anticipated, since self‐association was found in the form of a fibrin net‐like structure in TEM images. Betaine conjugates described herein open a new area of bioactive peptide foldamer construction, since the introduced quaternary charges may lead to important receptor‐ligand interactions, while potential material science applications can also be realized.