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 Aβ 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 Aβ(1–40) peptides, with sheets of parallel β-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 β-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 β-strands, and in the solvent-exposed N-terminal β-sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal β-sheets on top of each other. The interior C-terminal β-sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of Aβ fibrils.