Structural and Spectroscopic Studies of Peptoid Oligomers with α-Chiral Aliphatic Side Chains

Substantial progress has been made in the synthesis and characterization of various oligomeric
molecules capable of autonomous folding to well-defined, repetitive secondary structures. It is now possible
to investigate sequence−structure relationships and the driving forces for folding in these systems. Here,
we present detailed analysis by X-ray crystallography, NMR, and circular dichroism (CD) of the helical
structures formed by N-substituted glycine (or “peptoid”) oligomers with α-chiral, aliphatic side chains. The
X-ray crystal structure of a N-(1-cyclohexylethyl)glycine pentamer, the first reported for any peptoid, shows
a helix with cis-amide bonds, ∼3 residues per turn, and a pitch of ∼6.7 Å. The backbone dihedral angles
of this pentamer are similar to those of a polyproline type I peptide helix, in agreement with prior modeling
predictions. This crystal structure likely represents the major solution conformers, since the CD spectra of
analogous peptoid hexamers, dodecamers, and pentadecamers, composed entirely of either (S)-N-(1-cyclohexylethyl)glycine or (S)-N-(sec-butyl)glycine monomers, also have features similar to those of the
polyproline type I helix. Furthermore, this crystal structure is similar to a solution NMR structure previously
described for a peptoid pentamer comprised of chiral, aromatic side chains, which suggests that peptoids
containing either aromatic or aliphatic α-chiral side chains adopt fundamentally similar helical structures in
solution, despite distinct CD spectra. The elucidation of detailed structural information for peptoid helices
with α-chiral aliphatic side chains will facilitate the mimicry of biomolecules, such as transmembrane protein
domains, in a distinctly stable form.