Torsion angle based design of peptidomimetics: A dipeptidic template adopting β-I Turn (Ac-Aib-AzGly–NH 2)

Abstract

We have attempted to design a model dipeptide (acetyl dipeptide amide, Ac-CA1-CA2–NH 2) that can adopt specifically typical torsion angles of the β-I turn (φ i+1 , ψ i+1 , φ i+2 , ψ i+2 =−60°, −30°, −90°, 0°). The key of the design is the combination of constrained amino acids that prefer to adopt the desired torsion angles. We chose Aib (aminoisobutyric acid) as the first residue of which φ and ψ angles must be −60° and −30°, respectively. Then, we selected an azaamino acid as the second residue since previous studies have indicated that they prefer to adopt ±90° of φ angle and 0° or 180° of ψ angle. The conformational preference of the resulting Ac-Aib-AzGly–NH 2 is investigated using ab initio methods. The conformations implying β-I and β-I′ turns are energetically most favorable, as we expected. Thus, we synthesized the designed molecule on the solid phase considering the future generation of combinatorial libraries using an automatic peptide synthesizer. Then, NMR spectroscopy was carried out to confirm their conformational preference in solution was carried out. The results indicated that the Ac-Aib-AzGly–NH 2 adopt β-I or β-I′ turns in solution forming an intramolecular hydrogen bonding between Ac–C(O) and terminal NH 2. We believe that such a small peptidomimetic template is highly useful for the design of drug candidates and molecular devices.