title: Structure and dynamics of parallel beta-sheets, hydrophobic core, and loops in Alzheimer's A beta fibrils.
abstract: We explore the relative contributions of different structural elements to the stability of Abeta fibrils by molecular-dynamics simulations performed over a broad range of temperatures (298 K to 398 K). Our fibril structures are based on solid-state nuclear magnetic resonance experiments of Abeta(1-40) peptides, with sheets of parallel beta-strands connected by loops and stabilized by interior salt bridges. We consider models with different interpeptide interfaces, and different staggering of the N- and C-terminal beta-strands along the fibril axis. Multiple 10-20 ns molecular-dynamics simulations show that fibril segments with 12 peptides are stable at ambient temperature. The different models converge toward an interdigitated side-chain packing, and present water channels solvating the interior D23/K28 salt bridges. At elevated temperatures, we observe the early phases of fibril dissociation as a loss of order in the hydrophilic loops connecting the two beta-strands, and in the solvent-exposed N-terminal beta-sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal beta-sheets on top of each other. The interior C-terminal beta-sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of Abeta fibrils.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520.
authors.forename: Nicolae-Viorel
authors.initials: NV
authors.lastname: Buchete
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hummer
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)