Effect of Lauric Acid on the Stability of Aβ42 Oligomers

Abstract

While Alzheimer's disease is correlated with the presence of Aβ fibrils in patient brains, the more likely agents are their precursors, soluble oligomers that may form pores or otherwise distort cell membranes. Using all-atom molecular dynamics simulation, we study how the presence of fatty acids such as lauric acid changes the stability of pore-forming oligomers built from three-stranded Aβ₄₂ chains. Such a change would alter the distribution of amyloids in the fatty acid-rich brain environment and therefore could explain the lower polymorphism observed in Aβ fibrils derived from brains of patients with Alzheimer's disease. We find that lauric acid stabilizes both ring-like and barrel-shaped models, with the effect being stronger for barrel-like models than for ring-like oligomers.

Figure 1

Average number of inter-layer and side-wise (within a layer) inter-chain contacts as a function of time for Model A ring-like oligomers with (a,b) IRF or (c,d) ORF β₂–β₃-sheet arrangements. Averages are taken over all three runs simulated for each system and normalized in such a way that the corresponding value at the start is unity. The results for the total number of contacts are shown in black (in the presence of lauric acid) and green (in the absence of lauric acid), while the corresponding numbers of only native contacts are displayed in red (in the presence of lauric acid) and blue (in the absence of lauric acid).

Figure 2

Average number of inter-layer and side-wise (within a layer) inter-chain contacts as a function of time for model B ring-like oligomers with (a,b) IRF or (c,d) ORF β₂–β₃-sheet arrangements. Averages are taken over the three runs simulated for each system and normalized in such a way that the corresponding value at the start is unity. The results for the total number of contacts are shown in black (in the presence of lauric acid) and green (in the absence of lauric acid), while the corresponding numbers of only native contacts are displayed in red (in the presence of lauric acid) and blue (in the absence of lauric acid).

Figure 3

rmsd for the starting configuration as a function of time for the tetramer barrel (BB4) (a) in the presence of lauric acid and (b) in the absence of lauric acid. Results for the hexamer barrel (BB6) in the presence of lauric acid are shown in (c), and the ones taken in the absence of lauric acid are shown in (d).

Figure 4

Representative snapshots as obtained at the end of 200 ns simulated trajectories for the tetramer barrel (BB4) (a) in the presence or (b) absence of lauric acid. For comparison, we show also the starting configuration in (c). Similar configurations are shown for the hexamer (BB6) in (d–f), respectively. The N-terminals of each of the individual chains are marked as blue spheres.

Figure 5

Residue-wise root-mean-square fluctuations (rmsf) of (a) tetramer (BB4) (b) hexamer (BB6) barrel structures formed by Aβ₄₂ peptides in the presence (black) or in the absence (red) of lauric acid molecules bound to the starting configuration. The vertical lines show the error bar as calculated over the three independent simulations.

Figure 6

Distribution of pore distortion parameter (D_p, as defined in the text) for (a) the tetramer (BB4) and (b) the hexamer (BB6) barrel, as obtained from the last 100 ns trajectories of all three trial runs. The solid line represents data in the presence of lauric acid, while the dashed line indicates the data in the absence of lauric acid.

Figure 7

Distribution of the number of (a–c) intra-monomer and (d–f) inter-monomer side-chain contacts for the tetramer BB4 (shown in black) and the hexamer BB6 (shown in red). The solid line represents the data in the presence of lauric acid, while the dashed line indicates the data in the absence of lauric acid. The results are presented considering different parts of the monomers: top row (all residues), middle row (residues 11–42), and bottom row (residues 27–42).

Figure 8

Contact correlation function for (a–c) intra- and (d–f) inter-monomer side-chain contacts. Data for the tetramer (BB4) are drawn in black, and such for the hexamer (BB6) in red. Data from systems simulated in the presence of lauric acid are drawn as solid lines, while such from simulations without added lauric acid are drawn as dashed lines. Results are shown considering either all residues (top row), only residues 11–42 (middle row), or residues 27–42 (bottom row).

Figure 9

Residue-wise binding probability (normalized) of lauric acid for the tetramer (BB4) and hexamer (BB6) barrel structures. Data are calculated from the last 100 ns of all three independent runs in which the respective system was simulated.

Figure 10

Starting configurations for the ring-like model A oligomer with (a) in-register β₂–β₃ strands and (b) out-of-register β₂–β₃ strands; the ring-like model B oligomer with (c) in-register β₂–β₃ strands and (d) out-of-register β₂–β₃ strands; (e) the barrel-shaped tetramer BB4, and (f) the barrel-shaped hexamer BB6. The systems are simulated both in the absence and presence of lauric acid, with the binding sites of the fatty acids (as determined by Autodock) also shown in red color. The N-terminal ends of the individual chains are marked as spheres in blue.