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

Abstract

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.