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. 2008 Nov;4(11):e1000222.
doi: 10.1371/journal.pcbi.1000222. Epub 2008 Nov 14.

A generic mechanism of emergence of amyloid protofilaments from disordered oligomeric aggregates

Stefan Auer  1 , Filip Meersman, Christopher M Dobson, Michele Vendruscolo
Affiliations

A generic mechanism of emergence of amyloid protofilaments from disordered oligomeric aggregates

Stefan Auer et al. PLoS Comput Biol. 2008 Nov.

Abstract

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention because it has been associated with a range of neurodegenerative conditions including Alzheimer's and Parkinson's diseases. We provide a description of a sequence-indepedent mechanism by which polypeptide chains aggregate by forming metastable oligomeric intermediate states prior to converting into fibrillar structures. Our results illustrate that the formation of ordered arrays of hydrogen bonds drives the formation of beta-sheets within the disordered oligomeric aggregates that form early under the effect of hydrophobic forces. Individual beta-sheets initially form with random orientations and subsequently tend to align into protofilaments as their lengths increase. Our results suggest that amyloid aggregation represents an example of the Ostwald step rule of first-order phase transitions by showing that ordered cross-beta structures emerge preferentially from disordered compact dynamical intermediate assemblies.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Illustration of the self-assembly process of peptides into amyloid-like assemblies.
All simulations were carried out at a concentration c = 12.5 mM and reduced temperature T* = 0.66. The progress variable t corresponds to the number of Monte Carlo moves performed in the simulation, and one unit of t is a series of 105 Monte Carlo moves. Initially, at t = 1000 (A), all peptides are in a solvated state. As the simulation progresses, at t = 5000 (B), a hydrophobic collapse causes the formation of a disordered oligomer, which subsequently undergoes a structural reorganization into an amyloid-like assembly, at t = 30 000 (C), driven by the formation of ordered arrays of hydrogen bonds. Peptides that do not form intermolecular hydrogen bonds are shown in blue, while peptides that form intermolecular hydrogen bonds are assigned a random color, which is the same for peptides that belong to same β-sheet.
Figure 2
Figure 2. Time series of the energy per peptide as a function of the progress variable (t).
Together with the total energy (red line), we show the contributions from the hydrogen bonding energy (blue line), and the hydrophobic energy (black line). The gradual emergence of the cross-β ordering from the initially disordered oligomeric assemblies is characterised by a significant increase in the weight of the hydrogen bonding energy. Errorbars represent standard deviations over 11 independent trajectories. Representative structures formed during the process of conversion of the disordered oligomer into an amyloid-like structure are also shown at t = 5000, t = 15 000, and t = 30 000. The color code is as in Figure 1.
Figure 3
Figure 3. Histogram of the number Nn of β-sheets consisting of n peptides at four successive stages of the growth and reordering process of the oligomeric assembly shown in Figure 1: (A) t = 10 000, (B) t = 15 000, (C) t = 20 000, (d) t = 30 000).
This plot shows how β-sheet assemblies are progressively formed by the growth and alignment of individual β-sheets. At t = 10 000 (A) there are six β-sheets of sizes ranging from 3 to 16, whereas at t = 30 000 (D), there are nine β-sheets of sizes ranging from 8 to 42. If β-sheets are aligned so that the angle between them is smaller than 20 degrees, they are considered to form a protofilament-like structure, and the corresponding bars in the histogram are shown with the same color, as for instance in the case of the red assembly (Figure 1c, right), formed by four β-sheets of size 8, 19, 38, and 42.
Figure 4
Figure 4. Analysis of the evolution of the structure of the oligomers over 11 independent simulations.
(A) Development of the fraction of polypeptide chains in a oligomer (black), fraction of polypeptide chains in a oligomer that form a β-sheet conformation (blue), fraction of hydrogen bonds in a oligomer in a α-helical conformation (orange), and in a β-sheet conformation (red), or otherwise (green). (B) Development of the distribution function of the average number of β-sheets 〈Nn〉 of size n at t = 1000 (black), t = 5000 (red), t = 30 000 (blue). (C) Distribution function 〈Nl〉 of the number of protofilaments composed of l layers at t = 1000 (black), t = 15 000 (red), t = 30 000 (blue).
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