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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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Related in: MedlinePlus

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.
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pcbi-1000222-g001: 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.

Mentions: In this work we consider a system containing 216 12-residue homopolymers that exibit an α-helical native state below the folding temperature () and an undfolded structure at higher temperatures (see Materials and Methods for the definition of the temperature scale used here). Peptides that form native α-helical conformations [29], as well as homopolymeric sequences [30], have been shown to be able to form amyloid assemblies. In order to investigate the self-assembly of the peptides into fibrils we chose thermodynamic conditions such that fibril formation occurs on a timescale accessible to our simulations. We found that a peptide concentration c = 12.5 mM is above the critical concentration for aggregation, for temperatures below T* = 0.69. All our simulations were performed at T* = 0.66, and several independent starting configurations were generated at T* = 0.75. As in our simulations we set , the peptides were unfolded most of the time. A typical trajectory observed in our Monte Carlo simulations (see Materials and Methods) is illustrated in Figure 1.


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

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

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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2572140&req=5

pcbi-1000222-g001: 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.
Mentions: In this work we consider a system containing 216 12-residue homopolymers that exibit an α-helical native state below the folding temperature () and an undfolded structure at higher temperatures (see Materials and Methods for the definition of the temperature scale used here). Peptides that form native α-helical conformations [29], as well as homopolymeric sequences [30], have been shown to be able to form amyloid assemblies. In order to investigate the self-assembly of the peptides into fibrils we chose thermodynamic conditions such that fibril formation occurs on a timescale accessible to our simulations. We found that a peptide concentration c = 12.5 mM is above the critical concentration for aggregation, for temperatures below T* = 0.69. All our simulations were performed at T* = 0.66, and several independent starting configurations were generated at T* = 0.75. As in our simulations we set , the peptides were unfolded most of the time. A typical trajectory observed in our Monte Carlo simulations (see Materials and Methods) is illustrated in Figure 1.

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