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.
Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.