Conformational preferences of peptide-peptoid hybrid oligomers.

Abstract

Peptomers are oligomeric molecules composed of both α-amino acids and N-substituted glycine monomers, thus creating a hybrid of peptide and peptoid units. Peptomers have been used in several applications such as antimicrobials, protease inhibitors, and antibody mimics. Despite the considerable promise of peptomers as chemically diverse molecular scaffolds, we know little about their conformational tendencies. This lack of knowledge limits the ability to implement computational approaches for peptomer design. Here we computationally evaluate the local structural propensities of the peptide-peptoid linkage. We find some general similarities between the peptide residue conformational preferences and the Ramachandran distribution of residues that precede proline in folded protein structures. However, there are notable differences. For example, several β-turn motifs are disallowed when the i+2 residue is also a peptoid monomer. Significantly, the lowest energy geometry, when dispersion forces are accounted for, corresponds to a "cis-Pro touch-turn" conformation, an unusual turn motif that has been observed at protein catalytic centers and binding sites. The peptomer touch-turn thus represents a useful design element for the construction of folded oligomers capable of molecular recognition and as modules in the assembly of structurally complex peptoid-protein hybrid macromolecules.