Torsion angle based design of peptidomimetics: A dipeptidic template adopting beta-I turn (Ac-Aib-AzGly-NH2)

Abstract

We have attempted to design a model dipeptide (acetyl dipeptide amide, Ac-CA1-CA2-NH2) that can adopt specifically typical torsion angles of the beta -I turn (phi (i+1), psi (i+1), phi (i+2) psi (i+2) = -60 degrees, -30 degrees, -90 degrees, 0 degrees). 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 phi and psi angles must be -60 degrees and -30 degrees, respectively. Then, we selected an azaamino acid as the second residue since previous studies have indicated that they prefer to adopt +/- 90 degrees of phi angle and 0 degrees or 180 degrees of psi angle. The conformational preference of the resulting Ac-Aib-AzGly-NH2 is investigated using ab initio methods. The conformations implying beta -I and beta -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-NH2 adopt beta -I or beta -I' turns in solution forming an intramolecular hydrogen bonding between Ac-C(O) and terminal NH2. We believe that such a small peptidomimetic template is highly useful for the design of drug candidates and molecular devices. (C) 2001 Elsevier Science Ltd. All rights reserved.