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Destabilization of the 310-Helix in Peptides Based on Cα-Tetrasubstituted α-Amino Acids by Main-Chain to Side-Chain Hydrogen Bonds

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journal contribution
posted on 30.10.1998, 00:00 by Wojciech M. Wolf, Marcin Stasiak, Miroslav T. Leplawy, Alberto Bianco, Fernando Formaggio, Marco Crisma, Claudio Toniolo
The homooligopeptide series based on O,O-isopropylidene-α-hydroxymethylserine from dimer through pentamer has been synthesized to examine the conformational preferences of this new Cα-tetrasubstituted α-amino acid characterized by concomitant Ciα ↔ Ciα cyclization and presence of two ether oxygen atoms in the γ-positions of the six-membered ring 1,3-dioxane system. To this aim we have exploited X-ray diffraction in the crystal state and FTIR absorption and 1H NMR techniques in solution. The results obtained are compared with those of the homooligopeptides based on the related cyclohexane-containing Cα-tetrasubstituted residue. We conclude that in the former peptides a competition takes place between the classical intramolecular (peptide) CO···H−N (peptide) H-bonds, stabilizing the β-bend/310-helical structures, and the newly discovered (peptide) Ni+1−H···Oiγ (side-chain ether) intramolecular H-bonds. The extent of regular (incipient) 310-helix formation, where this latter type of H-bond is absent, tends to increase as peptide main-chain length increases. As a result of this intramolecular N−H···Oγ interaction, the critical main-chain length for 310-helix formation in the crystal state shifts from the shortest possible oligomer, the terminally protected trimer, in the cyclohexane series to the pentamer in the 1,3-dioxane series. Interestingly, a strict correlation has been found between the observed (peptide) Ni+1−H···Oiγ (side-chain ether) intramolecular H-bond and (i) the backbone ψ torsion angle of the i residue (extended), and (ii) the disposition of the α-amino substituent in the 1,3-dioxane ring of the i + 1 residue (axial).

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