Engineering β-sheets employing N-methylated heterochiral amino acids

Abstract

There is a lack of functional group diversity in the reverse turn motifs nucleating a β-sheet conformation in designed peptides, proteins and foldamers. The majority of these sequences consist of D-Pro–L-Pro, D-Pro–Gly or Asn–Gly as the turn inducing motif restricting their biological application and physicochemical modulation. In this report, for the first time we elucidate that N-methylation of heterochiral amino acids in linear peptides nucleates β-sheet conformation without the necessity of having a ring or covalent constraint at the reverse turn. Our results show that D-Pro can be conveniently substituted by any other N-methylated D-amino acid followed by an N-methylated L-amino acid or sarcosine to adopt a βII′ turn inducing the β-sheet folding. Furthermore, we reveal that a single amino acid either at the i + 1 or i + 2 site of the reverse turn can modulate the right-handed twist, which eventually dictates the extent of the foldedness of the β-hairpin.