Extraordinarily robust polyproline type I peptoid helices generated via the incorporation of α-chiral aromatic N-1-naphthylethyl side chains

Abstract

Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and, consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homo-oligomers by X-ray crystallography, NMR spectroscopy, and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 Å. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide K(cis/trans) values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homo-oligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.

Figure 1

(A) Comparison of the primary structures of an α-peptoid to an α-peptide. (B) N-substituted glycine side chains discussed in this study.

Figure 2

X-ray crystal structures of peptoids 1′ and 2–4. (A) View perpendicular to the helical axis. (B) View parallel to the helical axis. Atom designations: red = oxygen; blue = nitrogen; gray = carbon. Hydrogen atoms in (A) and (B) and the t-butyl methyl groups in (B) have been removed for clarity.

Figure 3

CD spectra of peptoids 1–4 at ~60 μM in acetonitrile. Spectra were collected at 24 °C.

Figure 4

CD spectra of peptoids 4–8 and 5′ at ~60 μM in acetonitrile. Spectra were collected at 24 °C.

Figure 5

CD spectra of peptoids 8–13 at ~60 μM in acetonitrile. Spectra were collected at 24 °C.

Figure 6

CD spectra of peptoid 13 at ~60 μM in acetonitrile. Data were collected between 5–75 °C in 10 ° increments.

Figure 7

CD spectra of peptoids 3, 6, 9, and 12 at ~60 μM in methanol. Spectra were collected at 24 °C.