title: 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.
authors.affiliation: Center for Fundamental and Applied Molecular Evolution, NSF/NASA Center for Chemical Evolution, Departments of Chemistry and Biology, Atlanta, Georgia 30322, USA.
authors.forename: W Seth
authors.initials: WS
authors.lastname: Childers
authors.forename: Neil R
authors.initials: NR
authors.lastname: Anthony
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mehta
authors.forename: Keith M
authors.initials: KM
authors.lastname: Berland
authors.forename: David G
authors.initials: DG
authors.lastname: Lynn
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D008958:Models, Molecular; D043942:Nanotubes / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry*; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C417223:amyloid beta-protein (16-22)