Stability and structure of oligomers of the Alzheimer peptide Abeta16-22: from the dimer to the 32-mer

Abstract

Several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are associated with amyloid fibrils formed by different polypeptides. We probe the structure and stability of oligomers of different sizes of the fragment Abeta(16-22) of the Alzheimer beta-amyloid peptide using atomic-detail molecular dynamics simulations with explicit solvent. We find that only large oligomers form a stable beta-sheet aggregate, the minimum nucleus size being of the order of 8-16 peptides. This effect is attributed to better hydrophobic contacts and a better shielding of backbone-backbone hydrogen bonds from the solvent in bigger assemblies. Moreover, the observed stability of beta-sheet aggregates with a different number of layers can be explained on the basis of their solvent-accessible surface area. Depending on the stacking interface between the sheets, we observe straight or twisted structures, which could be linked to the experimentally observed polymorphism of amyloid fibrils. To compare our 32-mer structure to experimental data, we calculate its x-ray diffraction pattern. Good agreement is found between experimentally and theoretically determined reflections, suggesting that our model indeed closely resembles the structures found in vitro.

FIGURE 1

Possible stacking of two β-sheets of Aβ_16–22. (a) Parallel stacking; (b) antiparallel stacking. The fibril axis (z axis) is perpendicular to the paper plane. To generate antiparallel β-sheets, the next layer in z-direction is obtained from the represented one by a rotation of 180° around the x axis.

FIGURE 2

Dimer. (a) Snapshots of structures sampled during the simulation 2₃₀₀. Hydrophobic side chains are shown in white, Lys side chains in blue, Glu side chains in red, hydrogen bonds in orange. (b) β-sheet content (black, number of residues); polar contacts (green), hydrophobic contacts (blue). (c) Salt bridges between Lys¹ and Glu¹⁴ (black) and between Glu⁷ and Lys⁸ (red) over the first 30 ns of the simulation. The histograms of the minimal distance between the charged groups are shown as full lines, while the integrals are shown as broken lines.

FIGURE 3

Trimer. (a) Snapshots of structures sampled during the simulation 3₃₀₀ (same color-code as in Fig. 2). (b) β-sheet content of the two remaining peptides (black, number of residues); polar contacts of the detaching peptide (green), hydrophobic contacts of the detaching peptide (blue). (c) Salt bridges between peptide 1 and 2 (black) and between peptide 2 and 3 (red). The histograms of the minimal distance between the charged groups are given as full lines, while the integrals are given as broken lines.

FIGURE 4

Tetramer. Representative conformations from MD simulations. (a) Simulations starting from one sheet of four strands (4₃₀₀ and 4₃₄₈). (b) Simulations starting from a 2 × 2 arrangement (4₃₀₀/PAR_mixed and 4₃₄₈/PAR_mixed).

FIGURE 5

Simulation 16₃₀₀/PAR_KVFE. (a) β-sheet content (black, number of residues per peptide), RMSD of inner eight peptides (green, Å), and RMSD of outer eight peptides (blue) with respect to the average structure of the last 20 ns. (b) Water channels inside the aggregate during the simulation (water positions taken from 200 snapshots, sampling interval of 10 ps). Water shown in orange, hydrophobic residues in white, Lys in blue, Glu in red; hydrogens omitted for clarity. (c) One snapshot of the simulation, showing that the Aβ_16–22 peptides form a compact hydrophobic core. Same color code as in panel b.

FIGURE 6

Rearrangements of β-sheets with different stackings. (a) Twist of sheets (observed in 16₃₀₀/AP_LFA), (b) shift in z direction by one peptide (observed in 16₃₀₀/PAR_LFA), and (c) rotation of one sheet with respect to the second sheet (observed in 16₃₀₀/PAR_KVFE).

FIGURE 7

32-mer. (a) Snapshot from simulation 32₃₀₀/PAR_mixed. (b) Snapshot from simulation 32₃₄₈/PAR_mixed. (c) β-sheet content (solid line, number of residues per peptide) and RMSD from the average structure of sheets I–III during the last 27-ns of simulation 32₃₀₀/PAR_mixed (in Å). Sheets I–III (dark shaded line), sheet IV (light shaded line), and sheets I–III from 32₃₄₈/PAR_mixed (dashed line).

FIGURE 8

(a) Calculated x-ray diffraction pattern of the 32-mer, averaged over the last 26 ns of simulation 32₃₀₀/PAR_mixed (26 frames, sampling time 1 ns). (b) Equatorial (solid line) and meridional (dashed line) x-ray diffraction pattern extracted from the same calculation. The equatorial peak reflects the intersheet distance, while the meridional peak reflects the interpeptide distance.

FIGURE 9

Total SASA (in Ų) as a function of the number of peptides. The data points are extracted from the MD simulations, and linear fits are displayed for the single-layered (black) and double-layered (red, PAR_mixed stacking) structures. For the four-layered structure (green) only one long simulation has been performed. The SASA extracted from two short simulations of a 4 × 4 (green square) and of a 2 × 16 (red square) arrangement confirm our predictions. The blue curve corresponds to the empirical formula derived for oligomeric proteins (79).