Differential Effects of β3 - versus β2 -Amino Acid Residues on the Helicity and Recognition Properties of Bim BH3-Derived α/β-Peptides.

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 β3 -amino acids or cyclic β-amino acids, but the impact of incorporating β2 residues has received little attention. The effects of β2 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 (β3 vs. β2 substitution) was compared. Circular dichroism data suggest that β2 residues can be helix-destabilizing relative to β3 residues, although the size of this effect seems to depend on side chain identity. Binding data show that β3 →β2 substitution at sites that contact a partner protein, Bcl-xL , can influence affinity in a way that transcends effects on helicity.