Impact of γ-Amino Acid Residue Preorganization on α/γ-Peptide Foldamer Helicity in Aqueous Solution

alpha/gamma-Peptide foldamers containing either gamma(4)-amino acid residues or ring-constrained gamma-amino acid residues have been reported to adopt 12-helical secondary structure in nonpolar solvents and in the solid state. These observations have engendered speculation that the seemingly flexible gamma(4) residues have a high intrinsic helical propensity and that residue-based preorganization may not significantly stabilize the 12-helical conformation. However, the prior studies were conducted in environments that favor intramoleculai-E-bond formation. Here, we use 2D-NMR to compare the ability of gamma(4) residues and cyclic gamma residues, to support 12-helix formation in more challenging environments, methanol and water. Both y residue types support 12-helical folding methanol, but only the cyclically constrained.y residues promote helicity in water. These results demonstrate the importance of residue-based preorganization strategies for achieving stable folding among short foldamers iri aqueous solution.