Stabilities and conformations of Alzheimer's beta -amyloid peptide oligomers (Abeta 16-22, Abeta 16-35, and Abeta 10-35): Sequence effects

Abstract

Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer beta-sheet model. Under high temperature simulation conditions, our approach can test the stability of possible amyloid forms. Here, we report our study of oligomers of Alzheimer's amyloid beta-peptide (Abeta) fragments 16-22, 16-35, and 10-35 (abbreviated Abeta(16-22), Abeta(16-35), and Abeta(10-35), respectively). Our simulations indicate that an antiparallel beta-sheet orientation is the most stable for the Abeta(16-22), in agreement with a solid state NMR-based model [Balbach, J. J., Ishii, Y., Antzutkin, O. N., Leapman, R. D., Rizzo, N. W., et al. (2000) Biochemistry 39, 13748-13759]. A model with twenty-four Abeta(16-22) strands indicates a highly twisted fibril. Whereas the short Abeta(16-22) and Abeta(24-36) may exist in fully extended form, the linear parallel beta-sheets for Abeta(16-35) appear impossible, mainly because of the polar region in the middle of the 16-35 sequence. However, a bent double-layered hairpin-like structure (called hook) with the polar region at the turn forms parallel beta-sheets with higher stability. An intra-strand salt-bridge (D23-K28) stabilizes the bent hairpin-like hook structure. The bent double-beta-sheet model for the Abeta(10-35) similarly offers oligomer stability.

Fig 1.

Simulation of the peptide 16–22 fragment. Starting conformation and β-sheet orientations.

Fig 2.

(A) rmsds of trajectories compared with the starting conformation. (B) Trajectories of the potential energies in simulations of the Antiparallel 1, Antiparallel 2, and Parallel 3 models. (C) Radial (distance) distribution functions of salt bridges in the octamers simulated. The distances between the nitrogen (Lys-16) and carboxylate carbon (Glu-22) are monitored.

Fig 3.

Snapshots from the simulations of Aβ_16–22 fragment oligomers. (A) Parallel 2 model at 1.1 ns. (B) Parallel 3 model at 3 ns, run 2. Only one layer is shown for clarity. (C) Antiparallel 2 model at 4.2 ns, run 2. (D and E) The equilibrated structure of Antiparallel 3 24-mer at 2.5 ns. (D) A view perpendicular to the fibril axis. Backbone atoms are shown in color and Phe are shown in yellow. Other side chains are omitted for clarity. (E) A view along the fibril axis of the simulated structure. Only backbone atoms are shown for clarity.

Fig 4.

Radial (distance) distribution functions for the Cα-Cα and C(O)… C(O) separations in the β-sheet oligomers of (A) octamer Antiparallel 2 model. (B) 24-mer of antiparallel sheets.

Fig 5.

An illustration of the β-strand arrangements in the octameric models considered for the peptide 16–35 fragment. (A–D) Parallel β-sheet models with linear β-strands. (E) Parallel β-sheet with a bent hairpin-like hook conformation.

Fig 6.

Trajectories of the simulations of Aβ_16–35 fragment octamers.

Fig 7.

An illustration of the β-strand arrangements in the octameric models considered for the Aβ_10–35 fragment with a parallel β-sheet with bent hairpin-like hook conformation.

Fig 8.

(A and B) Trajectories of the simulations of Aβ_10–35 fragment octamers. (C) Radial (distance) distribution functions of salt bridges in the octamers simulated. The distances between the nitrogen (Lys-28) and carboxylate carbon (Asp-23) are monitored. (D and E) Radial (distance) distribution functions for the Cα-Cα and C(O)… C(O) separations in the bent β-sheet oligomers.