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

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

Molecular interactions of Alzheimer's Aβ protofilaments with lipid membranes

Amyloid fibrils and peptide oligomers play central roles in the pathology of Alzheimer's disease, type 2 diabetes, Parkinson's disease, Huntington's disease, and prion-related disease. Here, we investigate the molecular interactions between preformed amyloid β (Aβ) molecular protofilaments and lipid bilayer membranes, in the presence of explicit water molecules, using computational models and all-atom molecular dynamics. These interactions play an important role in the stability and function of both Aβ fibrils and the adjacent cellular membrane. Taking advantage of the symmetry-related and directional properties of the protofilaments, we build models that cover several relative protofilament-membrane orientations. Our molecular dynamics simulations reveal the relative contributions of different structural elements to the dynamics and stability of Aβ protofilament segments near membranes, and the first steps in the mechanism of fibril-membrane interactions. During this process, we observe a significant alteration of the side-chain contact pattern in protofilaments, although a fraction of the characteristic β-sheet content is preserved. As a major driving force, we identify the electrostatic interactions between Aβ charged side chains, including E22, D23, and K28, and lipid headgroups. Together with hydrogen bonding with atoms from lipid headgroups, these interactions can facilitate the penetration of hydrophobic C-terminal amino acids through the lipid headgroup region, which can finally lead both to further loss of the initial fibril structure and to local membrane-thinning effects. Our results may guide new experiments that could test the extent to which the structural features of water-formed amyloid fibrils are preserved, lost, or reshaped by membrane-mediated interactions.