Controlling the Helix Handedness of ααβ‐Peptide Foldamers through Sequence Shifting

Peptide foldamers containing both cis‐β‐aminocyclopentanecarboxylic acid and α‐amino acid residues combined in various sequence patterns (ααβ, αααβ, αβααβ, and ααβαααβ) were screened using CD and NMR spectroscopy for the tendency to form helices. ααβ‐Peptides were found to fold into an unprecedented and well‐defined 16/17/15/18/14/17‐helix. By extending the length of the sequence or shifting a fragment of the sequence from one terminus to another in ααβ‐peptides, the balance between left‐handed and right‐handed helix populations present in the solution can be controlled. Engineering of the peptide sequence could lead to compounds with either a strong propensity for the selected helix sense or a mixture of helical conformations of opposite senses. Rewinding peptides: Modification of the peptide termini through extension or sequence shifting enables control of the balance between right‐handed and left‐handed helices for ααβ‐peptide foldamers containing cis‐2‐aminocyclopentanecarboxylic acid (red).