title: Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding -In vitrocharacterization.
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 amyloidin vivothereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogs of p5 that modify helicity and chirality.
  
  
  METHODS
  Peptide-ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogs. 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 reagentsin vivo.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Departments of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA; Departments of Radiology, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
authors.affiliation: Departments of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.affiliation: Departments of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Wooliver
authors.affiliation: Departments of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.
authors.forename: Emily B
authors.initials: EB
authors.lastname: Martin
authors.affiliation: Center for Molecular Biophysics, Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, TN, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Departments of Surgery, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Heidel
authors.affiliation: Departments of Medicine, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA; Departments of Radiology, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
keywords: Amyloid binding; CD; Heparin; Molecular dynamics; Polybasic peptides; amino acid spacing