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

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.