title: Protofibril assemblies of the arctic, Dutch, and Flemish mutants of the Alzheimer's Abeta1-40 peptide.
abstract: Using a coarse-grained model of the Abeta peptide, we analyze the Arctic (E22G), Dutch (E22Q), and Flemish (A21G) familial Alzheimer's disease (FAD) mutants for any changes in the stability of amyloid assemblies with respect to the wild-type (WT) sequence. Based on a structural reference state of two protofilaments aligned to create the "agitated" protofibril as determined by solid-state NMR, we determine free energy trends for Abeta assemblies for the WT and FAD familial sequences. We find that the structural characteristics and oligomer size of the critical nucleus vary dramatically among the hereditary mutants. The Arctic mutant's disorder in the turn region introduces new stabilizing interactions that better align the two protofilaments, yielding a well-defined protofibril axis at relatively small oligomer sizes with respect to WT. By contrast, the critical nucleus for the Flemish mutant is beyond the 20 chains characterized in this study, thereby showing a strong shift in the equilibrium toward monomers with respect to larger protofibril assemblies. The Dutch mutant forms more ordered protofilaments than WT, but exhibits greater disorder in protofibril structure that includes an alternative polymorph of the WT fibril. An important conclusion of this work is that the Dutch mutant does not support the agitated protofibril assembly. We discuss the implications of the structural ensembles and free energy profiles for the FAD mutants in regards to interpretation of the kinetics of fibril assembly using chromatography and dye-binding experiments.
authors.affiliation: UCSF/UCB Joint Graduate Group in Bioengineering, Berkeley, California 94720, USA.
authors.forename: Nicolas Lux
authors.initials: NL
authors.lastname: Fawzi
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Kohlstedt
authors.forename: Yuka
authors.initials: Y
authors.lastname: Okabe
authors.forename: Teresa
authors.initials: T
authors.lastname: Head-Gordon
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D001110:Arctic Regions; D002845:Chromatography / Q000379:methods; D020022:Genetic Predisposition to Disease; D009682:Magnetic Resonance Spectroscopy; D015233:Models, Statistical; D008968:Molecular Conformation; D009154:Mutation; D009426:Netherlands; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; C078592:amyloid beta-protein (1-40)