A Peptoid Square Helix via Synergistic Control of Backbone Dihedral Angles

The continued expansion
of the fields of macromolecular chemistry
and nanoscience has motivated the development of new secondary structures
that can serve as architectural elements of innovative materials,
molecular machines, biological probes, and even commercial medicines.
Synthetic foldamers are particularly attractive systems for developing
such elements because they are specifically designed to facilitate
synthetic manipulation and functional diversity. However, relatively
few predictive design principles exist that permit both rational and
modular control of foldamer secondary structure, while maintaining
the capacity for facile diversification of displayed functionality.
We demonstrate here that the synergistic application of two such principles
in the design of peptoid foldamers yields a new and unique secondary
structure that we term an “η-helix” due to its
repeating turns, which are highly reminiscent of peptide β-turns.
Solution-phase structures of η-helices were obtained by simulated
annealing using NOE-derived distance restraints, and the NMR spectra
of a series of designed η-helices were altogether consistent
with the primary adoption of this structure. The structure is resilient
to solvent and temperature changes, and accommodates diversification
without requiring postsynthetic manipulation. The unique shape, broad
structural stability, and synthetic accessibility of η-helices
could facilitate their utilization in a wide range of applications.