The development of peptide
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-hairpins is problematic, because folding depends on the aminoacid sequence and changes to the sequence can significantly decrease folding. Robust
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-hairpins thatcan tolerate such changes are attractive tools for studying interactions involving protein
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-sheets anddeveloping inhibitors of these interactions. This paper introduces a new class of peptide models of protein
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-sheets that addresses the problem of separating folding from the sequence. These model
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-sheets aremacrocyclic peptides that fold in water to present a pentapeptide
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-strand along one edge; the other edgecontains the tripeptide
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-strand mimic Hao [
JACS 2000,
122, 7654] and two additional amino acids. Thepentapeptide and Hao-containing peptide strands are connected by two
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-linked ornithine (
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Orn) turns[
JACS 2003,
125, 876]. Each
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Orn turn contains a free
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-amino group that permits the linking of individualmodules to form divalent
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-sheets. These "cyclic modular
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-sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular
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-sheets
1a-1h containing sequences based on
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-amyloid and macrophage inflammatory protein 2 weresynthesized and characterized by
1H NMR. Linked cyclic modular
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-sheet
2, which contains two modulesof
1b, was also synthesized and characterized.
1H NMR studies show downfield
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-proton chemical shifts,
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Orn
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-proton magnetic anisotropy, and NOE cross-peaks that establish all compounds but
1c and
1g tobe moderately or well folded into a conformation that resembles a
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-sheet. Pulsed-field gradient NMRdiffusion experiments show little or no self-association at low (
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2 mM) concentrations. Changes to theresidues in the Hao-containing strands of
1c and
1g improve folding and show that folding of the structurescan be enhanced without altering the sequence of the pentapeptide strand. Well-folded cyclic modular
![](/images/gifchars/beta2.gif)
-sheets
1a,
1b, and
1f each have a phenylalanine directly across from Hao, suggesting that cyclic modular
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-sheets containing aromatic residues across from Hao are better folded.