Effects of chirality and side chain length in Cα,α-dialkylated residues on β-hairpin peptide folded structure and stability

Abstract

Strategic incorporation of achiral C_α,α-dialkylated amino acids with bulky substituents into peptides can be used to promote extended strand conformations and inhibit protein–protein interactions associated with amyloid formation. In this work, we evaluate the thermodynamic impact of chiral C_α,α monomers on folding preferences in such systems through introduction of a series of C_α-methylated and C_α-ethylated residues into a β-hairpin host sequence. Depending on stereochemical configuration of the artificial monomer and potential for additional hydrophobic packing, a C_α-ethyl-C_α-propyl glycine residue can provide similar or enhanced folded stability relative to an achiral C_α,α-diethyl analogue.