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

Auer S, Meersman F, Dobson CM, Vendruscolo M - PLoS Comput. Biol. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Self Organising Molecular Systems, University of Leeds, Leeds, United Kingdom. s.auer@leeds.ac.uk

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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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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pcbi-1000222-g004: 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).

Mentions: We generated and analyzed a total of 11 independent trajectories, which consistently appeared as the type shown in Figure 1, and showed the same quantitative overall behavior. Assemblies are initially formed through the disordered rapid assembly of partially folded peptides, which then reorganize into ordered β sheets. A quantitative analysis (Figure 4) of the reordering process shows that initially about 60% of the hydrogen bonds within the oligomers are formed in disordered intermolecular associations, whereas the remainder are involved in intramolecular interactions within the native α-helix conformation (Figure 4a). At later stages, a structural reorganization of the oligomers results in essentially all hydrogen bonds being involved in the cross-β structure. Thus, in agreement with experimental evidence [33]–[35], we found that the formation of disordered oligomers is primarily driven by hydrophobic effects, whereas a reorganisation driven by hydrogen bond formation is subsequently playing a major role in the formation of cross-β structure [16],[28]. The formation of ordered assemblies starts with the pairing of two peptides, from which larger β-sheets develop (Figure 4b). As the simulation progresses, the height of the peak in the size distribution function associated with single β-sheets decreases and multi-layer β sheets form, thus revealing the process of protofilament formation (Figure 4c). This observation complements and extends the analysis shown in Figure 3, which shows that the β sheets align as they grow in size.


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

Auer S, Meersman F, Dobson CM, Vendruscolo M - PLoS Comput. Biol. (2008)

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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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2572140&req=5

pcbi-1000222-g004: 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).
Mentions: We generated and analyzed a total of 11 independent trajectories, which consistently appeared as the type shown in Figure 1, and showed the same quantitative overall behavior. Assemblies are initially formed through the disordered rapid assembly of partially folded peptides, which then reorganize into ordered β sheets. A quantitative analysis (Figure 4) of the reordering process shows that initially about 60% of the hydrogen bonds within the oligomers are formed in disordered intermolecular associations, whereas the remainder are involved in intramolecular interactions within the native α-helix conformation (Figure 4a). At later stages, a structural reorganization of the oligomers results in essentially all hydrogen bonds being involved in the cross-β structure. Thus, in agreement with experimental evidence [33]–[35], we found that the formation of disordered oligomers is primarily driven by hydrophobic effects, whereas a reorganisation driven by hydrogen bond formation is subsequently playing a major role in the formation of cross-β structure [16],[28]. The formation of ordered assemblies starts with the pairing of two peptides, from which larger β-sheets develop (Figure 4b). As the simulation progresses, the height of the peak in the size distribution function associated with single β-sheets decreases and multi-layer β sheets form, thus revealing the process of protofilament formation (Figure 4c). This observation complements and extends the analysis shown in Figure 3, which shows that the β sheets align as they grow in size.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre for Self Organising Molecular Systems, University of Leeds, Leeds, United Kingdom. s.auer@leeds.ac.uk

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.

Show MeSH
Related in: MedlinePlus