Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding - In vitro characterization

Jonathan Wall, Angela Williams, Craig Wooliver, Emily Martin, Xiaolin Cheng, Robert Heidel, Stephen Kennel

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8 Citations (Scopus)

Abstract

Background Polybasic helical peptides, such as peptide p5, bind human amyloid extracts and synthetic amyloid fibrils. When radiolabeled, peptide p5 has been shown to specifically bind amyloid in vivo thereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogues of p5 that modify helicity and chirality. Methods Peptide-ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogues. The interaction of a subset of peptides was further studied by using molecular dynamics simulations. Results Disruption of the peptide helical structure reduced peptide binding to heparin and human amyloid extracts. The all-D enantiomer and the β-sheet-structured peptide bound all substrates as well as, or better than, p5. The interaction of helical and β-sheet structured peptides with Aβ fibrils was modeled and shown to involve both ionic and non-ionic interactions. Conclusions The α-helical secondary structure of peptide p5 is important for heparin and amyloid binding; however, helicity is not an absolute requirement as evidenced by the superior reactivity of a β-sheet peptide. The differential binding of the peptides with heparin and amyloid fibrils suggests that these molecular interactions are different. The all-D enantiomer of p5 and the β-sheet peptide are candidates for amyloid targeting reagents in vivo. General Significance Efficient binding of polybasic peptides with amyloid is dependent on the linearity of charge spacing in the context of an α-helical secondary structure. Peptides with an α-helix or β-sheet propensity and with similar alignment of basic residues is optimal.

Original languageEnglish (US)
Pages (from-to)89-99
Number of pages11
JournalBiochemistry and Biophysics Reports
Volume8
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

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Chirality
Ligands
Peptides
Amyloid
Heparin
Enantiomers
In Vitro Techniques
Molecular interactions
Molecular Dynamics Simulation
Molecular dynamics

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding - In vitro characterization",
abstract = "Background Polybasic helical peptides, such as peptide p5, bind human amyloid extracts and synthetic amyloid fibrils. When radiolabeled, peptide p5 has been shown to specifically bind amyloid in vivo thereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogues of p5 that modify helicity and chirality. Methods Peptide-ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogues. The interaction of a subset of peptides was further studied by using molecular dynamics simulations. Results Disruption of the peptide helical structure reduced peptide binding to heparin and human amyloid extracts. The all-D enantiomer and the β-sheet-structured peptide bound all substrates as well as, or better than, p5. The interaction of helical and β-sheet structured peptides with Aβ fibrils was modeled and shown to involve both ionic and non-ionic interactions. Conclusions The α-helical secondary structure of peptide p5 is important for heparin and amyloid binding; however, helicity is not an absolute requirement as evidenced by the superior reactivity of a β-sheet peptide. The differential binding of the peptides with heparin and amyloid fibrils suggests that these molecular interactions are different. The all-D enantiomer of p5 and the β-sheet peptide are candidates for amyloid targeting reagents in vivo. General Significance Efficient binding of polybasic peptides with amyloid is dependent on the linearity of charge spacing in the context of an α-helical secondary structure. Peptides with an α-helix or β-sheet propensity and with similar alignment of basic residues is optimal.",
author = "Jonathan Wall and Angela Williams and Craig Wooliver and Emily Martin and Xiaolin Cheng and Robert Heidel and Stephen Kennel",
year = "2016",
month = "12",
day = "1",
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language = "English (US)",
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pages = "89--99",
journal = "Biochemistry and Biophysics Reports",
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TY - JOUR

T1 - Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding - In vitro characterization

AU - Wall, Jonathan

AU - Williams, Angela

AU - Wooliver, Craig

AU - Martin, Emily

AU - Cheng, Xiaolin

AU - Heidel, Robert

AU - Kennel, Stephen

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background Polybasic helical peptides, such as peptide p5, bind human amyloid extracts and synthetic amyloid fibrils. When radiolabeled, peptide p5 has been shown to specifically bind amyloid in vivo thereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogues of p5 that modify helicity and chirality. Methods Peptide-ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogues. The interaction of a subset of peptides was further studied by using molecular dynamics simulations. Results Disruption of the peptide helical structure reduced peptide binding to heparin and human amyloid extracts. The all-D enantiomer and the β-sheet-structured peptide bound all substrates as well as, or better than, p5. The interaction of helical and β-sheet structured peptides with Aβ fibrils was modeled and shown to involve both ionic and non-ionic interactions. Conclusions The α-helical secondary structure of peptide p5 is important for heparin and amyloid binding; however, helicity is not an absolute requirement as evidenced by the superior reactivity of a β-sheet peptide. The differential binding of the peptides with heparin and amyloid fibrils suggests that these molecular interactions are different. The all-D enantiomer of p5 and the β-sheet peptide are candidates for amyloid targeting reagents in vivo. General Significance Efficient binding of polybasic peptides with amyloid is dependent on the linearity of charge spacing in the context of an α-helical secondary structure. Peptides with an α-helix or β-sheet propensity and with similar alignment of basic residues is optimal.

AB - Background Polybasic helical peptides, such as peptide p5, bind human amyloid extracts and synthetic amyloid fibrils. When radiolabeled, peptide p5 has been shown to specifically bind amyloid in vivo thereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogues of p5 that modify helicity and chirality. Methods Peptide-ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogues. The interaction of a subset of peptides was further studied by using molecular dynamics simulations. Results Disruption of the peptide helical structure reduced peptide binding to heparin and human amyloid extracts. The all-D enantiomer and the β-sheet-structured peptide bound all substrates as well as, or better than, p5. The interaction of helical and β-sheet structured peptides with Aβ fibrils was modeled and shown to involve both ionic and non-ionic interactions. Conclusions The α-helical secondary structure of peptide p5 is important for heparin and amyloid binding; however, helicity is not an absolute requirement as evidenced by the superior reactivity of a β-sheet peptide. The differential binding of the peptides with heparin and amyloid fibrils suggests that these molecular interactions are different. The all-D enantiomer of p5 and the β-sheet peptide are candidates for amyloid targeting reagents in vivo. General Significance Efficient binding of polybasic peptides with amyloid is dependent on the linearity of charge spacing in the context of an α-helical secondary structure. Peptides with an α-helix or β-sheet propensity and with similar alignment of basic residues is optimal.

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