Proteins and RNA are unique among known polymers in their ability to adopt compact and well-defined folding patterns. These two biopolymers can perform complex chemical operations such as catalysis and highly selective recognition, and these functions are linked to folding in that the creation of an active site requires proper juxtaposition of reactive groups. So the development of new types of polymeric backbones with well-defined and predictable folding propensities ('foldamers') might lead to molecules with useful functions. The first step in foldamer development is to identify synthetic oligomers with specific secondary structural preferences. Whereas alpha-amino acids can adopt the well-known alpha-helical motif of proteins, it was shown recently that beta-peptides constructed from carefully chosen beta-amino acids can adopt a different, stable helical conformation defined by interwoven 14-membered-ring hydrogen bonds (a 14-helix; Fig. 1a). Here we report that beta-amino acids can also be used to design beta-peptides with a very different secondary structure, a 12-helix (Fig. 1a). This demonstrates that by altering the nature of beta-peptide residues, one can exert rational control over the secondary structure.
Synthetic protocols and circular dichroism (CD) spectra are reported for a series of oligomers of
(R,R)-trans-2-aminocyclopentanecarboxylic acid (trans-ACPC). The two longest oligomers, a hexamer and
an octamer, have also been examined crystallographically. Both crystal structures show that the β-peptide
backbone adopts a regular helix that is defined by a series of interwoven 12-membered ring hydrogen bonds
(“12-helix”). Each hydrogen bond links a carbonyl oxygen to an amide proton three residues toward the
C-terminus. CD data suggest that the conformational preference of trans-ACPC oligomers in methanol is
strongly length-dependent, which implies that 12-helix formation is a cooperative process, as seen for the
α-helix formed by conventional peptides. Previous work has established that oligomers and polymers of β-amino
acids can adopt helical conformations, but the 12-helix is an unprecedented β-peptide secondary structure.
The preparation, crystal structures, and circular dichroism (CD) spectra of two oligomers of optically
active trans-2-aminocyclohexanecarboxylic acid are reported. In the solid state, both the tetramer and the
hexamer of this β-amino acid display a helical conformation that involves 14-membered-ring hydrogen bonds
between a carbonyl oxygen and the amide proton of the second residue toward the N-terminus. (For comparison,
the familiar α-helix observed in conventional peptides is associated with a 13-membered-ring hydrogen bond
between a carbonyl oxygen and the amide proton of the fourth residue toward the C-terminus.) These
crystallographic data, along with CD data obtained in methanol, suggest that the 14-helix constitutes a stable
secondary structure for β-amino acid oligomers (“β-peptides”). In addition, the crystal packing pattern observed
for the hexamer offers a blueprint for the design of β-peptides that might adopt a helical bundle tertiary structure.
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