Cyclic Modular -Sheets
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- 作者：R. Jeremy Woods ; Justin O. Brower ; Elena Castellanos ; Mehrnoosh Hashemzadeh ; Omid Khakshoor ; Wade A. Russu ; James S. Nowick
- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：March 7, 2007
- 年：2007
- 卷：129
- 期：9
- 页码：2548 - 2558
- 全文大小：404K
- 年卷期：v.129,no.9(March 7, 2007)
- ISSN：1520-5126
文摘
The development of peptide 
-hairpins is problematic, because folding depends on the aminoacid sequence and changes to the sequence can significantly decrease folding. Robust -hairpins thatcan tolerate such changes are attractive tools for studying interactions involving protein -sheets anddeveloping inhibitors of these interactions. This paper introduces a new class of peptide models of protein-sheets that addresses the problem of separating folding from the sequence. These model -sheets aremacrocyclic peptides that fold in water to present a pentapeptide -strand along one edge; the other edgecontains the tripeptide -strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. Thepentapeptide and Hao-containing peptide strands are connected by two 
-linked ornithine (Orn) turns[JACS 2003, 125, 876]. Each Orn turn contains a free 
-amino group that permits the linking of individualmodules to form divalent -sheets. These "cyclic modular -sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular-sheets 1a-1h containing sequences based on -amyloid and macrophage inflammatory protein 2 weresynthesized and characterized by 1H NMR. Linked cyclic modular -sheet 2, which contains two modulesof 1b, was also synthesized and characterized. 1H NMR studies show downfield -proton chemical shifts,Orn -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 -sheet. Pulsed-field gradient NMRdiffusion experiments show little or no self-association at low (
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-sheets 1a, 1b, and 1f each have a phenylalanine directly across from Hao, suggesting that cyclic modular-sheets containing aromatic residues across from Hao are better folded.
-hairpins is problematic, because folding depends on the aminoacid sequence and changes to the sequence can significantly decrease folding. Robust -hairpins thatcan tolerate such changes are attractive tools for studying interactions involving protein -sheets anddeveloping inhibitors of these interactions. This paper introduces a new class of peptide models of protein-sheets that addresses the problem of separating folding from the sequence. These model -sheets aremacrocyclic peptides that fold in water to present a pentapeptide -strand along one edge; the other edgecontains the tripeptide -strand mimic Hao [JACS 2000, 122, 7654] and two additional amino acids. Thepentapeptide and Hao-containing peptide strands are connected by two -linked ornithine (Orn) turns[JACS 2003, 125, 876]. Each Orn turn contains a free -amino group that permits the linking of individualmodules to form divalent -sheets. These "cyclic modular -sheets" are synthesized by standard solid-phase peptide synthesis of a linear precursor followed by solution-phase cyclization. Eight cyclic modular-sheets 1a-1h containing sequences based on -amyloid and macrophage inflammatory protein 2 weresynthesized and characterized by 1H NMR. Linked cyclic modular -sheet 2, which contains two modulesof 1b, was also synthesized and characterized. 1H NMR studies show downfield -proton chemical shifts,Orn -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 -sheet. Pulsed-field gradient NMRdiffusion experiments show little or no self-association at low (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-sheets 1a, 1b, and 1f each have a phenylalanine directly across from Hao, suggesting that cyclic modular-sheets containing aromatic residues across from Hao are better folded.