Phase Networks of Cross-β Peptide Assemblies

Abstract

Recent evidence suggests that simple peptides can access diverse amphiphilic phases, and that these structures underlie the robust and widely distributed assemblies implicated in nearly 40 protein misfolding diseases. Here we exploit a minimal nucleating core of the Aβ peptide of Alzheimer's disease to map its morphologically accessible phases that include stable intermolecular molten particles, fibers, twisted and helical ribbons, and nanotubes. Analyses with both fluorescence lifetime imaging microscopy (FLIM) and transmission electron microscopy provide evidence for liquid-liquid phase separations, similar to the coexisting dilute and dense protein-rich liquid phases so critical for the liquid-solid transition in protein crystallization. We show that the observed particles are critical for transitions to the more ordered cross-β peptide phases, which are prevalent in all amyloid assemblies, and identify specific conditions that arrest assembly at the phase boundaries. We have identified a size dependence of the particles in order to transition to the para-crystalline phase and a width of the cross-β assemblies that defines the transition between twisted fibers and helically coiled ribbons. These experimental results reveal an interconnected network of increasing molecularly ordered cross-β transitions, greatly extending the initial computational models for cross-β assemblies.

Shape selection and multi-stability in helical ribbons

“…The sophisticated interactions between elastic restoring forces, molecular orientations, chirality, or electrostatic interactions often lead to selection of different shapes, 8,[33][34][35][36][37] such as cylindrical helical ribbons and tubules with vanishing Gauss curvature, and twisted ribbons or straight helicoids with non-zero Gauss curvature. For example, peptides organized as bilayer membranes 38 form ribbons that coil into micron-long nanotubes, [39][40][41] and can transition reversibly between a purely twisted shape and a nanotube upon healing and cooling. 28 Moreover, the shape transition between twisted ribbons, two-dimensional disks, and double/triple helices can occur in colloidal membranes with the line tension tuned by molecular chirality.…”

“…39,51 In solution, this peptide assembles into purely twisted ribbons or cylindrical helical ribbons. 41 Since the Poisson's ratio is unavailable, we used three different values ( ¼ 0:1, 0.3, and 0.5). Fig.…”

Light and heat control over secondary structure and amyloid-like fiber formation in an overcrowded-alkene-modified Trp zipper

“…Probably the hybrid peptide goes through a phase transition phenomenon: the fibers are formed from vesicles as recently reported, for example, for the peptide Ac-KLVFFAE-NH 2 . 31 In our system it is possible to visualize this transition state, indicated with an arrow in Fig. 6b and detailed in Fig.…”

“…Importantly, cis - 1 in methanol forms structures typically associated with amyloidogenic peptides. 31 …”

Direct observation of closure domain wall mediated spin waves

“…The static elasticity models 21,22 cannot study the microscopic mechanism of the morphology transformation dynamics in peptide self-assembly but reveal the relation between morphology and the width, which have been confirmed by recent experiments. 26 Selinger et al 23 developed an elastic model to study morphological transformations of chiral molecules, which is, however, unsuitable for this study due to the lack of direct mapping between their molecular model and the peptide molecular structure. Aggeli's model 24,25 considered the peptide molecular structure appropriately, but it was designed to study the static conformations and cannot be used to study morphology transformation dynamic processes.…”