The beta-turn preferential solution conformation of a tetrapeptide containing an azaamino acid residue

The global minimum energy conformation of an azapeptide model, For-Ala-azaA la-NH2 was predicted by ab initio calculation of the 3-21G and 6-31G* level s. The backbone torsion angle (phi (1), psi (1), phi (2), psi (2)) of an az apeptide model appeared to be the P-turn conformation with a dihedral angle (-61 degrees, 131 degrees, 79 degrees, 15 degrees). This indicates that az aamino acid induces the beta -turn motif regardless of the change of chain length by the addition of an amino acid in azapeptide when compared with th e minimum energy conformation of For-azaAla-NH2. We designed and synthesize d a tetrapeptide containing azaamino acid, Boc-Ala-Phe-azaLeu-Ala-OMe (1) t o verify whether this beta -turn conformation is still conserved in solutio n. The solution conformation of this azapeptide model was determined by usi ng IR, NMR and molecular modeling techniques. The conformational behavior o f this azapeptide was compared with that of the tetrapeptide, Boc-Ala-Phe-L eu-Ala-OMe (2), which was not associated with azaamino acid. The IR evidenc e of intramolecular H-bonding, the characteristic nuclear Overhauser enhanc ement (NOE) patterns, the temperature coefficients of amide protons and sma ll solvent accessibility for the azapeptide 1 reveal that it favors the bet a -turn structure, whereas the peptide 2 forms extended structure in CDCl3 solution. The average structure of azapeptide I from a restrained molecular dynamics simulation indicated that the dihedral angles [(phi (2), psi (2)) , (phi (3), psi (3))] of Phe-azaLeu fragment in a model peptide, Boc-Ala-Ph e-azaLeu-Ala-OMe were [(-60 +/- 8 degrees, 125 +/- 24 degrees), (88 +/- 21 degrees, 1 +/- 4 degrees)], and this implies that the intercalation of an a zaamino acid residue in tetrapeptide induces the beta II-turn conformation, and the increase of chain length by the addition of an amino acid in azape ptide constituents would not disrupt the backbone dihedral angle of beta -t urn conformation. (C) 2001 Elsevier Science B.V. All rights reserved.