An unusual interstrand H-bond stabilizes the heteroassembly of helical αßγ-chimeras with natural peptides.

The substitution of α-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 α-helical peptide and an αßγ-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 α-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 ß/γ-segment. Gained results can be directly applied in the design of biologically relevant peptides containing ß- and γ-amino acids.