title: Spontaneous formation of twisted Aβ(16-22) fibrils in large-scale molecular-dynamics simulations.
abstract: Protein aggregation is associated with fatal neurodegenerative diseases, including Alzheimer's and Parkinson's. Mapping out kinetics along the aggregation pathway could provide valuable insights into the mechanisms that drive oligomerization and fibrillization, but that is beyond the current scope of computational research. Here we trace out the full kinetics of the spontaneous formation of fibrils by 48 Aβ(16-22) peptides, following the trajectories in molecular detail from an initial random configuration to a final configuration of twisted protofilaments with cross-β-structure. We accomplish this by performing large-scale molecular-dynamics simulations based on an implicit-solvent, intermediate-resolution protein model, PRIME20. Structural details such as the intersheet distance, perfectly antiparallel β-strands, and interdigitating side chains analogous to a steric zipper interface are explained by and in agreement with experiment. Two characteristic fibrillization mechanisms - nucleation/templated growth and oligomeric merging/structural rearrangement - emerge depending on the temperature.
authors.affiliation: Center for Proteome Biophysics, Department of Physics, Pusan National University, Busan, Korea.
authors.forename: Mookyung
authors.initials: M
authors.lastname: Cheon
authors.forename: Iksoo
authors.initials: I
authors.lastname: Chang
authors.forename: Carol K
authors.initials: CK
authors.lastname: Hall
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D053838:Scattering, Small Angle; D013696:Temperature; D013997:Time Factors; D014961:X-Ray Diffraction
chemical_list: D000596:Amino Acids; D016229:Amyloid beta-Peptides
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