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.