Figure 1.
Initial structures for dodecamer models.
Each dodecamer was assembled from symmetric hexamer subunits comprised of asymmetric dimers. The view is down the approximate 3-fold axis of the hexamer. C-terminal β-hairpins form a hydrophobic core and N-terminal residues are set to helical conformation. Met35 sulfur atoms are depicted as spheres. The relative position of these atoms helps to illustrate the structural variance between the models. The structures are rendered with MOE [31].
Figure 2.
Root-mean-square deviation (RMSD) from the initial structure.
Each model displays similar structural variance from the initial configuration. The RMSD for the core atoms rapidly achieves convergence of between 2 and 2.3 Å. The total RMSD shows a consistent increase in change due to the transition of the N-terminal helices to a random coil state. The trajectory of M1 was extended to 2 ns to illustrate that the equilibrium achieved by the core atoms is not impacted by N-terminal motions.
Figure 3.
Residue mobility as determined by average B-factors.
Values are averaged over all chains in the last 0.5 ns of the MD simulation. High fluctuations are noted for the unstable α helix. Residues in the core have low mobilities with central and C-terminal turn residues exhibiting higher values. The lower packing density of model M4 is reflected in significantly higher motions.
Table 1.
Ensemble averages of structural features in Aβ42 dodecamer models.
Figure 4.
Average amide proton solvent accessible surface area relative to tripeptide (rSASA).
The values are averaged over all chains. The N-terminus and central turn regions display a high degree of solvent exposure with lower values at the C-terminus, consistent with experimental H/D exchange trends. Higher values for residues in the middle of the N-terminal region would be expected as the helices transition to random coil.
Figure 5.
Atomic contact energies (ACE) for residues 30–42.
Values are determined from minimized trajectory endpoints and shown for each chain. A negative ACE value indicates hydrophobic stabilization. Large values are noted for sidechains defining the center of the dodecamer.
Table 2.
Energy contributions for core residues in optimized endpoint structures.
Figure 6.
Representative model of a PrPc complex with Aβ42 dimer.
The N terminus of the PrPc β-sheet is extended by 2 strands in a model of the double deletion mutant (Δ(51–91,111–125)). A model of Aβ42 dimer (G1) interacts with residues 97–100 of the extended β-sheet in an interfacial manner. The indole sidechain of W99 is shown for orientation. The figure is rendered with MOE [31].