title: Molecular dynamics simulations of Alzheimer's beta-amyloid protofilaments.
abstract: Filamentous amyloid aggregates are central to the pathology of Alzheimer's disease. We use all-atom molecular dynamics (MD) simulations with explicit solvent and multiple force fields to probe the structural stability and the conformational dynamics of several models of Alzheimer's beta-amyloid fibril structures, for both wild-type and mutated amino acid sequences. The structural models are based on recent solid state NMR data. In these models, the peptides form in-register parallel beta-sheets along the fibril axis, with dimers of two U-shaped peptides located in layers normal to the fibril axis. Four different topologies are explored for stacking the beta-strand regions against each other to form a hydrophobic core. Our MD results suggest that all four NMR-based models are structurally stable, and we find good agreement with dihedral angles estimated from solid-state NMR experiments. Asp23 and Lys28 form buried salt-bridges, resulting in an alternating arrangement of the negatively and positively charged residues along the fibril axis that is reminiscent of a one-dimensional ionic crystal. Interior water molecules are solvating the buried salt-bridges. Based on data from NMR measurements and MD simulations of short amyloid fibrils, we constructed structural models of long fibrils. Calculated X-ray fiber diffraction patterns show the characteristics of packed beta-sheets seen in experiments, and suggest new experiments that could discriminate between various fibril topologies.
authors.affiliation: Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.
authors.forename: Nicolae-Viorel
authors.initials: NV
authors.lastname: Buchete
authors.forename: Robert
authors.initials: R
authors.lastname: Tycko
authors.forename: Gerhard
authors.initials: G
authors.lastname: Hummer
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D011487:Protein Conformation; D014961:X-Ray Diffraction
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments