A peptoid ribbon secondary structure.

foldamers that have been shown to possess numerous biological functions and could find use in a range of fundamental and applied contexts as bio-inspired materials. Peptoids are highly attractive scaffolds for such purposes, as their non-native backbones are resistant to proteolytic degradation and their straightforward, modular synthesis enables the ready incorporation of a range of structurally diverse amide side chains. However, the design and prediction of peptoid secondary or higher-order structure remains a major challenge, and few discrete structures have been characterized to date for acyclic peptoids. This paucity of structure–function data limits the potential utility of peptoids, despite their many advantages. Structural studies of peptoids have been largely thwarted by the intrinsic conformational flexibility of the peptoid backbone itself. This backbone contains C-amethylene units, lacks hydrogen bond donating atoms, and, perhaps most notably, is linked by tertiary amides that can be isoenergetic between cis and trans amide geometries (Figure 1b). We and others reasoned that the development of peptoid side chains capable of engendering a high degree of control over proximate main-chain amide geometries could facilitate the design of well-defined peptoid structures and expand our understanding of peptoid folding. We recently designed and synthesized a range of peptoid model systems to test this hypothesis, and have identified several classes of amide side chains that favor cis or trans main-chain amides in peptoid oligomers, predominantly through steric and stereoelectronic effects. One such side chain is the a-chiral aromatic (S)-1-(1naphthyl)ethyl (s1npe) group (Figure 1), which strongly favors cis amide bonds (cis/trans> 6.3:1) in peptoid model systems. Moreover, Ns1npe homooligomers adopt polyproline type I (PPI)-like peptoid helices that contain exclusively cis amides in the peptoid main chain. In turn, we found that the trans amide peptoid rotamer is strongly enforced by Naryl side chains (for example, Nph, cis/trans< 0.05:1; Figure 1), and homooligomers of these residues have been calculated to give rise to extended, polyproline type II (PPII)like peptoid helices with all trans amides. These peptoid monomers are thus a set of building blocks with which to initiate a rational construction of new peptoid secondary structures. Herein, we report our first test of this modular design strategy for peptoids and our ensuing discovery of a new secondary structure containing an alternating sequence of aromatic residues that we designate as the “peptoid ribbon”. In view of the strong rotameric preferences enforced inNaryl and Ns1npe monomers, we hypothesized that linear peptoids containing an alternating sequence of these two residues would adopt a well-defined and novel secondary structure with a regular, alternating pattern of trans and cis main-chain amides. A recent X-ray crystallographic report of an N-aryl/Ns1npe dimer by Kirshenbaum and co-workers showed that the N-aryl amide bond was trans and that the Ns1npe amide bond was cis, and served to support our design hypothesis. The only known a-peptide sequences that adopt a regular, alternating pattern of trans/cis backbone Figure 1. a) The primary structure of an a-peptoid oligomer (dihedral angles omega (w), phi (f), psi (y), and chi (c) labeled) and the structures of the peptoid side chains discussed in this study. Sidechain abbreviations: s1npe= (S)-1-(1-naphthyl)ethyl; ph=phenyl; 2,6 mph=2,6-dimethylphenyl; 3,5 mph=3,5-dimethylphenyl; 4fph=4fluorophenyl. b) Peptoid cis and trans amide rotamers and the isomeric preferences engendered by the two amide side chains investigated in this study in model peptoid monomer systems.