Crystal-state conformation of Cα,α-dialkylated peptides containing chiral β-homo-residues

Secondary structure formation and stability are essential features in the knowledge of complex folding topology of biomolecules. To better understand the relationships between preferred conformations and functional properties of beta -homo-amino acids, the synthesis and conformational characterization by X-ray diffraction analysis of peptides containing conformationally constrained C-alpha,C-alpha-dialkylated amino acid residues, such as alpha -aminoisobutyric acid or 1-aminocyclohexane-1-carboxylic acid and a single beta -homo-amino acid, differently displaced along the peptide sequence have been carried out. The peptides investigated are: Boc-beta HLeu-(Ac(6)c)(2)-OMe, Boc-Ac(6)c-beta HLeu-(Ac(6)c)(2)-OMe and Boc-beta HVal-(Aib)(5)-OtBu, together with the C-protected beta -homo-residue HCl .H beta HVal-OMe. The results indicate that the insertion of a betaH-residue at position 1 or 2 of peptides containing strong helix-inducing, bulky C-alpha,C-alpha-disubstituted amino acid residues does not Induce any specific conformational preferences. In the crystal state, most of the NH groups of beta -homo residues of tri- and tetrapeptides are not involved in intramolecular hydrogen bonds, thus failing to achieve helical structures similar to those of peptides exclusively constituted of C-alpha,C-alpha-disubstituted amino acid residues. However, by repeating the structural motifs observed in the molecules investigated, a beta -pleated sheet secondary structure, and a new helical structure, named (14/15)-helix, were generated, corresponding to calculated minimum-energy conformations. Our findings, as well as Literature data, strongly indicate that conformations of betaH-residues, with the mu torsion angle equal to - 60 degrees, are very unlikely.