Macrocyclic β-sheet peptides that mimic protein quaternary structure through intermolecular β-sheet interactions

Omid Khakshoor, Borries Demeler, James S. Nowick

Research output: Contribution to journalArticle

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Abstract

This paper reports the design, synthesis, and characterization of a family of cyclic peptides that mimic protein quaternary structure through β-sheet interactions. These peptides are 54-membered-ring macrocycles comprising an extended heptapeptide β-strand, two Hao β-strand mimics [JACS 2000, 122, 7654] joined by one additional α-amino acid, and two δ-linked ornithine β-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 β-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 β-sheet dimers. In this tetrameric β-sheet sandwich, the macrocyclic peptide 3a is folded to form a β-sheet, the β-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.

Original languageEnglish (US)
Pages (from-to)5558-5569
Number of pages12
JournalJournal of the American Chemical Society
Volume129
Issue number17
DOIs
StatePublished - May 2 2007

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Quaternary Protein Structure
Peptides
Proteins
Cyclic Peptides
Dimers
Oligomerization
Dimerization
Oligomers
Protein Multimerization
Nuclear magnetic resonance
Ornithine
Ultracentrifugation
Amino acids

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Macrocyclic β-sheet peptides that mimic protein quaternary structure through intermolecular β-sheet interactions. / Khakshoor, Omid; Demeler, Borries; Nowick, James S.

In: Journal of the American Chemical Society, Vol. 129, No. 17, 02.05.2007, p. 5558-5569.

Research output: Contribution to journalArticle

Khakshoor, Omid ; Demeler, Borries ; Nowick, James S. / Macrocyclic β-sheet peptides that mimic protein quaternary structure through intermolecular β-sheet interactions. In: Journal of the American Chemical Society. 2007 ; Vol. 129, No. 17. pp. 5558-5569.
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abstract = "This paper reports the design, synthesis, and characterization of a family of cyclic peptides that mimic protein quaternary structure through β-sheet interactions. These peptides are 54-membered-ring macrocycles comprising an extended heptapeptide β-strand, two Hao β-strand mimics [JACS 2000, 122, 7654] joined by one additional α-amino acid, and two δ-linked ornithine β-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 β-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 β-sheet dimers. In this tetrameric β-sheet sandwich, the macrocyclic peptide 3a is folded to form a β-sheet, the β-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.",
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