Spontaneous self-assembly of amyloid β (1-40) into dimers

Abstract

The self-assembly and fibrillation of amyloid β (Aβ) proteins is the neuropathological hallmark of Alzheimer's disease. However, the molecular mechanism of how disordered monomers assemble into aggregates remains largely unknown. In this work, we characterize the assembly of Aβ (1-40) monomers into dimers using long-time molecular dynamics simulations. Upon interaction, the monomers undergo conformational transitions, accompanied by change of the structure, leading to the formation of a stable dimer. The dimers are stabilized by interactions in the N-terminal region (residues 5-12), in the central hydrophobic region (residues 16-23), and in the C-terminal region (residues 30-40); with inter-peptide interactions focused around the N- and C-termini. The dimers do not contain long β-strands that are usually found in fibrils.

Fig. 1. Time-resolved change in protein secondary structure during 4 μs all-atom MD simulations of Aβ40 dimers in the orthogonal (a) and parallel (b) starting configurations. Red and blue depict data using a running average filter. Right column shows a snapshot of the initial structures for each system.

Fig. 2. Analysis of Aβ40 dimers obtained from 3 μs aggregate accelerated MD simulations. Top, free energy landscape based on dihedral principle component analysis of Aβ40 dimers; the two lowest energy structures are shown as cartoons. Blue depict monomer 1 while red is monomer 2. Bottom, probability of each secondary structure type, determined by DSSP, for each monomer within the Aβ40 dimer, on a per residue basis.

Fig. 3. Cluster analysis of Aβ40 dimers obtained from 3 μs aggregate accelerated MD simulations. Representative structures of the top 20 clusters formed by Aβ40 dimers are presented with relative populations, as percent, for each cluster displayed below each structure. α-Helices are colored blue while β-strands are in red. A solid sphere depicts the N-terminal Cα.

Fig. 4. Analysis of peptide interactions of Aβ40 dimers from 3 μs aggregate accelerated MD. (a) The difference in the contact probability between the two monomers and (b) the inter-peptide contact probability map for Cα atoms of dimers.

Fig. 5. Force-induced dissociation results for Aβ40 dimers obtained from experiment (from ref. 11) and MCP simulations. Each dataset shows a scatter plot of normalized distance vs. force, a histogram of force (blue), and a histogram of normalized distance (red); normalization was performed based on the experimentally observed contour lengths. Peak values, obtained using Gaussian distribution function, are presented above each peak of the histogram. Cluster 01 and 02 are conformations from Fig. 3, while “MD” is the most populated cluster following MD simulation. Statistical analysis was performed using two-sample Kolmogorov–Smirnov test with 0.05 significance level; only cluster 01 was statistically similar to the experimental data set, with p > 0.066.