A Peptoid Ribbon Secondary Structure

Abstract

Delineating the relationships between sequence, structure, and function in biopolymers is critical to our understanding of fundamental biochemical interactions. These relationships are equally important for the design of functional biomimetic oligomers (that is, foldamers). [1] Oligomers of N-substituted glycine, or peptoids (Figure 1 a), [2] are an important class of foldamers that have been shown to possess numerous biological functions [3] and could find use in a range of fundamental and applied contexts as bio-inspired materials. [4] Peptoids are highly attractive scaffolds for such purposes, as their non-native backbones are resistant to proteolytic degradation [5] and their straightforward, modular synthesis [6] enables the ready incorporation of a range of structurally diverse amide side chains. [7] 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. [8] 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-a methylene 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 1 b). 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. [9] 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. [9c] Moreover, Ns1npe homooligomers adopt polyproline type I (PPI)-like peptoid helices that contain exclusively cis amides in the peptoid main chain. [8e] 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. [9b] 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 rotameri...

Aromatic Residue Positioning Influences Helical Peptoid Structure in Aqueous Solution

“…1 2 Moreover, peptoids can overcome peptides’ pharmacokinetic liabilities: peptoids exhibit proteolytic stability, 3 are not immunogenic, 4 and have useful cell permeability properties. 5 Importantly, peptoids that emulate conformational features of peptides, including helices, 6 7 8 9 10 11 12 sheets, 13 and turns, 14 have been described as well as peptoids that adopt abiological folds. 15 16 17 Of these, a peptoid helix that resembles the polyproline type I (PPI) helix 6 is among the most well-studied structures.…”

“…5 Importantly, peptoids that emulate conformational features of peptides, including helices, 6 7 8 9 10 11 12 sheets, 13 and turns, 14 have been described as well as peptoids that adopt abiological folds. 15 16 17 Of these, a peptoid helix that resembles the polyproline type I (PPI) helix 6 is among the most well-studied structures. Water-soluble PPI helical peptoids have found application as antimicrobials, 18 19 20 for example, and modulating the secondary structure has been shown to impact the selectivity for bacterial cells over eukaryotic cells.…”