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

backgroundPolybasic 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

methodsPeptide-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.

resultsDisruption 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.

conclusionsThe 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 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.