Helix Formation in α,γ- and β,γ-Hybrid Peptides: Theoretical Insights into Mimicry of α- and β-Peptides

Abstract

α,γ- and β,γ-hybrid peptides, which are composed of two different homologous amino acid constituents in alternate order, are suggested as novel classes of peptide foldamers. On the basis of a systematic conformational search employing the methods of ab initio MO theory, the possibilities for the formation of periodic secondary structures in these systems are described. The conformational analysis provides a great number of helix conformers widely differing in energy, which can be arranged into three groups: (i) helices with all hydrogen bonds formed in forward direction along the sequence, (ii) helices with all hydrogen bonds in backward direction, and (iii) helices with alternate hydrogen-bond directions (mixed or β-helices). Most stable are representatives of β-helices, but their stability decreases considerably in more polar environments in comparison to helix conformers from the other two classes. There is a great similarity between the overall topology of the most stable hybrid peptide helices and typical helices of peptides which are exclusively composed of a single type of homologous amino acids. Thus, the helices of the β,γ-hybrid peptides mimic perfectly those of the native α-peptides as, for instance, the well-known α-helix, whereas the most stable helix conformers of α,γ-hybrid peptides correspond well to the overall structure of β-peptide helices. The two suggested novel hybrid peptide classes expand considerably the pool of peptide foldamers and may be promising tools in peptide design and in material sciences.