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

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.