Abstract
Oligomers containing α- and β-amino acid residues (α/β-peptides) have been shown to mimic the α-helical conformation of conventional peptides when the unnatural residues are derived from β(3) -amino acids or cyclic β-amino acids, but the impact of incorporating β(2) residues has received little attention. The effects of β(2) residues on the conformation and recognition behavior of α/β-peptides that mimic an isolated α-helix were investigated. This effort has focused on 26-mers based on the Bim BH3 domain; a set of isomers with identical α/β backbones that differ only in the placement of certain side chains along the backbone (β(3) vs. β(2) substitution) was compared. Circular dichroism data suggest that β(2) residues can be helix-destabilizing relative to β(3) residues, although the size of this effect seems to depend on side chain identity. Binding data show that β(3) →β(2) substitution at sites that contact a partner protein, Bcl-x(L) , can influence affinity in a way that transcends effects on helicity.