title: Probing the structural determinants of type II' beta-turn formation in peptides and proteins.
abstract: The structural determinants of type II' beta-turns were probed through a comprehensive CD, NMR, and molecular dynamics analysis of 10 specially designed beta-hairpin peptides. The peptide model used in this study is a synthetic, water-soluble, 14-residue cyclic analogue of gramicidin S which contains two well-defined type II' beta-turns connected by a highly stable, amphipathic, antiparallel beta-sheet. A variety of coded and noncoded amino acids were systematically substituted in one of the two type II' turns to analyze the effects of backbone chirality, side-chain steric restriction, and side-chain/side-chain interactions. beta-Sheet content (as measured through a variety of experimental methods), molecular dynamics, and 3D structural analysis of the turn regions were used to assess the effects of each amino acid substitution on type II' beta-turn stabilization. Our results demonstrate that backbone heterochirality, which determines equatorial and axial side-chain orientation at the i+1 and i+2 residues of type II' turns, may account for up to 60% of type II' beta-turn stabilization. Steric restriction through side-chain N-alkylation appears to enhance type II' beta-turn propensity and may account for up to 20% of type II' beta-turn stabilization. Finally, aromatic/proline side-chain interactions appear to account for approximately 10% of type II' beta-turn stabilization. We believe this information could be particularly useful for the prediction of beta-turn propensity, the development of peptide-based drugs, and the de novo design of peptides, proteins, and peptidyl mimetics.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Gibbs
authors.forename: Trent C
authors.initials: TC
authors.lastname: Bjorndahl
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hodges
authors.forename: David S
authors.initials: DS
authors.lastname: Wishart
mesh_terms: D002942:Circular Dichroism; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D009842:Oligopeptides