Structure and dynamics of parallel β-sheets, hydrophobic core, and loops in Alzheimer's Aβ fibrils

We explore the relative contributions of different structural elements to the stability of A beta 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 A beta(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 A beta fibrils.