Crystal-state conformation of C-alpha,C-alpha-dialkylated peptides containing chiral beta-homo-residues

Secondary structure formation and stability are essential features in the k nowledge 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 characterizati on by X-ray diffraction analysis of peptides containing conformationally co nstrained C-alpha,C-alpha-dialkylated amino acid residues, such as alpha -a minoisobutyric acid or 1-aminocyclohexane-1-carboxylic acid and a single be ta -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 o f peptides containing strong helix-inducing, bulky C-alpha,C-alpha-disubsti tuted amino acid residues does not Induce any specific conformational prefe rences. 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 e xclusively constituted of C-alpha,C-alpha-disubstituted amino acid residues . However, by repeating the structural motifs observed in the molecules inv estigated, a beta -pleated sheet secondary structure, and a new helical str ucture, named (14/15)-helix, were generated, corresponding to calculated mi nimum-energy conformations. Our findings, as well as Literature data, stron gly indicate that conformations of betaH-residues, with the mu torsion angl e equal to - 60 degrees, are very unlikely. Copyright (C) 2001 European Pep tide Society and John Wiley & Sons, Ltd.