title: Macrocyclic beta-sheet peptides that mimic protein quaternary structure through intermolecular beta-sheet interactions.
abstract: This paper reports the design, synthesis, and characterization of a family of cyclic peptides that mimic protein quaternary structure through beta-sheet interactions. These peptides are 54-membered-ring macrocycles comprising an extended heptapeptide beta-strand, two Hao beta-strand mimics [JACS 2000, 122, 7654] joined by one additional alpha-amino acid, and two delta-linked ornithine beta-turn mimics [JACS 2003, 125, 876]. Peptide 3a, as the representative of these cyclic peptides, contains a heptapeptide sequence (TSFTYTS) adapted from the dimerization interface of protein NuG2 [PDB ID: 1mio]. 1H NMR studies of aqueous solutions of peptide 3a show a partially folded monomer in slow exchange with a strongly folded oligomer. NOE studies clearly show that the peptide self-associates through edge-to-edge beta-sheet dimerization. Pulsed-field gradient (PFG) NMR diffusion coefficient measurements and analytical ultracentrifugation (AUC) studies establish that the oligomer is a tetramer. Collectively, these experiments suggest a model in which cyclic peptide 3a oligomerizes to form a dimer of beta-sheet dimers. In this tetrameric beta-sheet sandwich, the macrocyclic peptide 3a is folded to form a beta-sheet, the beta-sheet is dimerized through edge-to-edge interactions, and this dimer is further dimerized through hydrophobic face-to-face interactions involving the Phe and Tyr groups. Further studies of peptides 3b-3n, which are homologues of peptide 3a with 1-6 variations in the heptapeptide sequence, elucidate the importance of the heptapeptide sequence in the folding and oligomerization of this family of cyclic peptides. Studies of peptides 3b-3g show that aromatic residues across from Hao improve folding of the peptide, while studies of peptides 3h-3n indicate that hydrophobic residues at positions R3 and R5 of the heptapeptide sequence are important in oligomerization.
authors.affiliation: Department of Chemistry, University of California-Irvine, Irvine, California 92697-2025, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Khakshoor
authors.forename: Borries
authors.initials: B
authors.lastname: Demeler
authors.forename: James S
authors.initials: JS
authors.lastname: Nowick
mesh_terms: D003500:Cyclization; D047028:Macrocyclic Compounds / Q000138:chemical synthesis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013056:Spectrophotometry, Ultraviolet; D014461:Ultracentrifugation; D014867:Water / Q000737:chemistry
chemical_list: D047028:Macrocyclic Compounds; D010455:Peptides; D014867:Water