title: Positional screening and NMR structure determination of side-chain-to-side-chain cyclized β3-peptides.
abstract: Many β-peptides fold in a 14-helical secondary structure in organic solvents, but similar 14-helix formation in water requires additional stabilizing elements. Especially the 14-helix stabilization of short β-peptides in aqueous solution is critical, due to the limited freedom for incorporating stabilizing elements. Here we show how a single lactam bridge, connecting two β-amino acid side-chains, can lead to high 14-helix character in short β(3)-peptides in water. A comparative study, using CD and NMR spectroscopy and structure calculations, revealed the strong 14-helix inducing power of a side-chain-to-side-chain cyclization and its optimal position on the β(3)-peptide scaffold with respect to pH and ionic strength effects. The lactam bridge is ideally incorporated in the N-terminal region of the β(3)-peptide, where it limits the conformational flexibility of the peptide backbone. The lactam bridge induces a 14-helical conformation in methanol and water to a similar extent. Based on the presented first high resolution NMR 3D structure of a lactam bridged β(3)-peptide, the fold shows a large degree of high order, both in the backbone and in the side-chains, leading to a highly compact and stable folded structure.
authors.affiliation: Max Planck Institute of Molecular Physiology, Otto-Hahn Strasse 11, 44227, Dortmund, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Vaz
authors.forename: Sonja A
authors.initials: SA
authors.lastname: Dames
authors.forename: Matthias
authors.initials: M
authors.lastname: Geyer
authors.forename: Luc
authors.initials: L
authors.lastname: Brunsveld
mesh_terms: D000595:Amino Acid Sequence; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D009842:Oligopeptides