Foldameric β‐H18/20_P Mixed Helix Stabilized by Head‐to‐Tail Contacts: A Way to Higher‐Order Structures

Abstract

Peptidic foldamers are known to exhibit increased diversity in the periodic secondary‐structure space in comparison with their natural counterparts, but their higher‐order self‐organization has been studied less thoroughly. In theory, large‐diameter peptide foldamer helices have the capability of self‐recognition through axial helix–helix interactions (e.g., head‐to‐tail), but this phenomenon has previously been observed in only one instance. In this article we report on the discovery of the largest‐diameter β‐peptidic mixed helix to date, the H18/20P helix. Its formation is solvent‐dependent and its folding occurs cooperatively through head‐to‐tail self‐assembly in solution. These findings suggest that axial helix–helix interactions can serve as a new mode for the formation of tertiary/quaternary structures for peptide foldamers, which also show higher‐order structural diversity than natural proteins.

Heterogeneous H-Bonding in a Foldamer Helix

“…Thus, for example, an α/β-peptide contains H-bond accepting groups (C=O) and donating groups (N-H) from both α and β residues. Different types of H-bonds are found also in foldameric helices in which H-bond directionality alternates along the backbone, whether the backbone is homogeneous (as in the β-peptide 10/12-helix 7 and 18/20-helix 8 ) or heterogeneous (as in the α/β-peptide 11/9-helix 9 and 18/16-helix 10 ). These systems raise a fundamental question: are the different types of intrahelical H-bonds comparably favorable?…”

Sequence Engineering to Control the Helix Handedness of Peptide Foldamers

“…However, conformational preferences could be effectively modulated by incorporation of constrained amino acids. The effect of shifting the sequence of a peptide composed of conformationally constrained cis ‐ACPC residues with alternating chirality was shown by Martinek and co‐workers . Compound 3 forms a right‐handed 10/12‐helix, while shifting one residue between the termini produces the enantiomeric structure 4 with the opposite handedness (Figure ).…”

Environmental Effects Determine the Structure of Potential β‐Amino Acid Based Foldamers

“…The effect of the medium on the structure of β‐peptide foldamers has been rarely studied in any detail . One of the few examples related with β‐peptidic foldamers is an oligomer with the largest turn known to date (H18/20), and whose secondary structure has been shown to exhibit solvent dependence when switching from methanol to DMSO . The scarcity of studies related to the dependence of folding on the environment could be traced back to the notion that this kind of foldamers have an intrinsic propensity to fold, and that the folding rules are written in its monomer sequence .…”