Engineering beta-sheets employing N-methylated heterochiral amino acids

There is a lack of functional group diversity in the reverse turn motifs nucleating a beta-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 b-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 beta II' turn inducing the b-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 beta-hairpin