Stabilizing unusual conformations in small peptides and glucopeptides using a hydroxylated cyclobutane amino acid

Abstract

The synthesis and the conformational study in the solid state and in aqueous solution of a peptide and a glucopeptide containing the non-natural (1S,2S)-1-amino-2-hydroxycyclobutanecarboxylic acid (c₄Ser) residue are reported. This is the first example of a glycopeptide containing a carbohydrate moiety linked to an underlying non-natural amino acid residue. The conformational analysis in solution combines NOEs and coupling constants data with Molecular Dynamics (MD) simulations with time-averaged restraints. The study reveals that the c₄Ser-Ala-Ala diamide peptide shows a conformation of two consecutive β-turn type III structures (the basic structural element of a 3₁₀ helix). However, none of the turns observed in the peptide are present in the derived glucopeptide. The influence of the carbohydrate moiety on the peptide backbone can be explained by means of the existence of two simultaneous hydrogen bonds, between the endocyclic oxygen of the glucose and two amidic protons of the peptide. In addition, the non-natural residue favors the existence of an unusual high energy conformation for the glycosidic linkage, the so-called anti-ϕ conformation.