title: Protofilaments, filaments, ribbons, and fibrils from peptidomimetic self-assembly:  implications for amyloid fibril formation and materials science.
abstract: Deciphering the mechanism(s) of β-sheet mediated self-assembly is essential for understanding amyloid fibril formation and for the fabrication of polypeptide materials. Herein, we report a simple peptidomimetic that self-assembles into polymorphic β-sheet quaternary structures including protofilaments, filaments, fibrils, and ribbons that are reminiscent of the highly ordered structures displayed by the amyloidogenic peptides Aβ, calcitonin, and amylin. The distribution of quaternary structures can be controlled by and in some cases specified by manipulating the pH, buffer composition, and the ionic strength. The ability to control β-sheet-mediated assembly takes advantage of quaternary structure dependent pK(a) perturbations. Biophysical methods including analytical ultracentrifugation studies as well as far-UV circular dichroism and FT-IR spectroscopy demonstrate that linked secondary and quaternary structural changes mediate peptidomimetic self-assembly. Electron and atomic force microscopy reveal that peptidomimetic assembly involves numerous quaternary structural intermediates that appear to self-assemble in a convergent fashion affording quaternary structures of increasing complexity. The ability to control the assembly pathway(s) and the final quaternary structure(s) afforded should prove to be particularly useful in deciphering the quaternary structural requirements for amyloid fibril formation and for the construction of noncovalent macromolecular structures.
authors.affiliation: Contribution from the Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB12, La Jolla, California 92037, and Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, United Kingdom.
authors.forename: H A
authors.initials: HA
authors.lastname: Lashuel
authors.forename: S R
authors.initials: SR
authors.lastname: Labrenz
authors.forename: L
authors.initials: L
authors.lastname: Woo
authors.forename: L C
authors.initials: LC
authors.lastname: Serpell
authors.forename: J W
authors.initials: JW
authors.lastname: Kelly