Protofilaments, Filaments, Ribbons, and Fibrils from Peptidomimetic Self-Assembly:  Implications for Amyloid Fibril Formation and Materials Science

Abstract

Deciphering the mechanism(s) of -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 -sheet quaternary structures including protofilaments, filaments, fibrils, and ribbons that are reminiscent of the highly ordered structures displayed by the amyloidogenic peptides A , 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 -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.The self-assembly of peptides and proteins into noncovalent -sheet rich quaternary structures, including fibrils, has attracted the attention of numerous laboratories owing to their association with neurodegenerative disease and their interesting structures. [1][2][3][4][5][6][7][8][9][10] In both amyloid and prion diseases a normally soluble protein or proteolytic fragment undergoes a conformational change either prior to, or coincident with, its self-assembly into -sheet rich fibrils, implicated as the causative agent in numerous neurodegenerative diseases by genetic linkage. [11][12][13][14][15][16][17][18][19] Previous studies on amyloid fibril assembly establish the presence of quaternary structural intermediates, which appear to undergo convergent assembly into intermediates of increasing complexity until amyloid fibrils are ultimately afforded. [20][21][22][23][24][25][26][27][28] The differing quaternary structures observed could explain the strains char- ‡ Laboratory of Molecular Biology. (3) Yamada, N.; Katsuhiko, A.; Naito, M.; Matsubara, K.; Koyama, E. J. Am. Chem. Soc. 1998, 120, 12192-12199. (4) Janek, K.; Behlke, J.; Zipper, J.; Fabian, H.; Georgalis, Y.; Beyemmann, M.; Bienert, M.; Krause, E.

Amyloid Fibril Formation from Sequences of a Natural β-Structured Fibrous Protein, the Adenovirus Fiber

“…The electron microscopy and fiber diffraction measurements suggest that the structural features of the fibrils formed from these peptides are similar to those described previously for disease-related amyloid structures. Furthermore, striking similarities are observed with fibrils formed from peptidomimetic compounds (48) and de novo designed peptides (49). It is interesting to note that our EM and fiber diffraction results are not in full agreement.…”

Simulations of nucleation and elongation of amyloid fibrils

“…48 Our model can naturally apply to the case of flat-ribbonlike amyloid fibrils, 19,22,[49][50][51] with possible extension to twisted ribbons 6,24,35,[50][51][52] or coiled helical structure with constant interacting regions ͓Fig. 6͑a͒ of Ref.…”

β-Sheet peptide-assisted polymerization of diacetylene at the air–water interface and thermochromic property

“…Langmuir monolayers of b-sheet peptides were, for example, reported to function as templates and serve as nuclei for the formation of inorganic nanocrystallites at the air-water interface. 12 Recently, numerous research groups have demonstrated that amphiphilic peptides self-assemble into b-sheet nanofiber architectures, [13][14][15][16][17][18][19][20] the surface of which has potential as a novel nanotemplate. [21][22][23] Several groups [24][25][26][27] have separately used b-sheet peptide nanofibers as templates to organize diacetylenes or dienes and promote their topochemical polymerization.…”