Exploiting Amyloid Fibril Lamination for Nanotube Self-Assembly

Fundamental questions about the relative arrangement of the β-sheet arrays within amyloid fibrils remain central to both its structure and the mechanism of self-assembly. Recent computational analyses suggested that sheet-to-sheet lamination was limited by the length of the strand. On the basis of this hypothesis, a short seven-residue segment of the Alzheimer's disease-related Aβ peptide, Aβ(16−22), was allowed to self-assemble under conditions that maintained the basic amphiphilic character of Aβ. Indeed, the number increased over 20-fold to 130 laminates, giving homogeneous bilayer structures that supercoil into long robust nanotubes. Small-angle neutron scattering and X-ray scattering defined the outer and inner radii of the nanotubes in solution to contain a 44-nm inner cavity with 4-nm-thick walls. Atomic force microscopy and transmission electron microscopy images further confirmed these homogeneous arrays of solvent-filled nanotubes arising from a flat rectangular bilayer, 130 nm wide × 4 nm thick, with each bilayer leaflet composed of laminated β-sheets. The corresponding backbone H-bonds are along the long axis, and β-sheet lamination defines the 130-nm bilayer width. This bilayer coils to give the final nanotube. Such robust and persistent self-assembling nanotubes with positively charged surfaces of very different inner and outer curvature now offer a unique, robust, and easily accessible scaffold for nanotechnology

Cross-Strand Pairing and Amyloid Assembly

Amino acid cross-strand pairing interactions along a β-sheet surface have been implicated in protein β-structural assembly and stability, yet the relative contributions have been difficult to evaluate directly. Here we develop the central core sequence of the Aβ peptide associated with Alzheimer’s disease, Aβ(16−22), as an experimental system for evaluating these interactions. The peptide allows for internal comparisons between electrostatic and steric interactions within the β-sheet and an evaluation of these cross-strand pair contributions to β-sheet registry. A morphological transition from fibers to hollow nanotubes arises from changes in β-sheet surface complementarity and provides a convenient indicator of the β-strand strand registry. The intrinsic β-sequence and pair correlations are critical to regulate secondary assembly. These studies provide evidence for a critical desolvation step that is not present in most models of the nucleation-dependent pathway for amyloid assembly

Cross-Strand Pairing and Amyloid Assembly

Amino acid cross-strand pairing interactions along a β-sheet surface have been implicated in protein β-structural assembly and stability, yet the relative contributions have been difficult to evaluate directly. Here we develop the central core sequence of the Aβ peptide associated with Alzheimer’s disease, Aβ(16−22), as an experimental system for evaluating these interactions. The peptide allows for internal comparisons between electrostatic and steric interactions within the β-sheet and an evaluation of these cross-strand pair contributions to β-sheet registry. A morphological transition from fibers to hollow nanotubes arises from changes in β-sheet surface complementarity and provides a convenient indicator of the β-strand strand registry. The intrinsic β-sequence and pair correlations are critical to regulate secondary assembly. These studies provide evidence for a critical desolvation step that is not present in most models of the nucleation-dependent pathway for amyloid assembly

Nucleobase-Directed Amyloid Nanotube Assembly

Nucleobase-Directed Amyloid Nanotube Assembl

Facial Symmetry in Protein Self-Assembly

Amyloids are self-assembled protein architectures implicated in dozens of misfolding diseases. These assemblies appear to emerge through a “selection” of specific conformational “strains” which nucleate and propagate within cells to cause disease. The short Aβ(16−22) peptide, which includes the central core of the Alzheimer’s disease Aβ peptide, generates an amyloid fiber which is morphologically indistinguishable from the full-length peptide fiber, but it can also form other morphologies under distinct conditions. Here we combine spectroscopic and microscopy analyses that reveal the subtle atomic-level differences that dictate assembly of two conformationally pure Aβ(16−22) assemblies, amyloid fibers and nanotubes, and define the minimal repeating unit for each assembly