An Unusual Interstrand H-Bond Stabilizes the Heteroassembly of Helical αβγ-Chimeras with Natural Peptides

The substitution of alpha-amino acids by homologated amino acids has a strong impact on the overall structure and topology of peptides, usually leading to a loss in thermal stability. Here, we report on the identification of an ideal core packing between an alpha-helical peptide and an alpha beta gamma-chimera via phage display. Selected peptides assemble with the chimeric sequence with thermal stabilities that are comparable to that of the parent bundle consisting purely of alpha-amino acids. With the help of MD simulations and mutational analysis this stability could be explained by the formation of an interhelical H-bond between the selected cysteine and a backbone carbonyl of the beta/gamma-segment. Gained results can be directly applied in the design of biologically relevant peptides containing beta- and gamma-amino acids.