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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

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.
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pcbi-1000222-g002: 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.

Mentions: We systematically observed a rapid collapse of the peptides into disordered aggregates that subsequently underwent a structural reorganization and transform into cross-β protofilaments (Figure 1). These results are consistent with a previously described two-step condensation-ordering mechanism [16],[18],[28], which has also been observed experimentally [9]. A plot of the total energy per peptide as a function of the progress variable t (Figure 2) shows that the final structure has a much lower energy than the initial and intermediate states. The major contribution to this energy comes from hydrogen bonding (Figure 2), a result consistent with the recent report that the hydrogen bonding energy provides the dominant factor stabilising the cross-β architecture is represented by hydrogen bonding, while in more disordered states other contributions are also important [31]. The initial state (t<1000), before the hydrophobic collapse, in which all peptides are solvated, has the highest energy and it is unstable. After the hydrophobic collapse has taken place (1000<t<5000), the peptides form a disordered oligomer, which is characterised by similar contributions from hydrophobic interactions and hydrogen bonding (Figure 2); this oligomeric state is lower in energy but metastable with respect to the amyloid state. Finally, with the growth of the cross-β architecture the hydrogen bonding interactions become progressively dominant (Figure 2). The survival time of the disordered oligomeric state is rather short (about 10–15% of the total simulation time) since in order to be able to investigate the self-assembly of the peptides we chose thermodynamic conditions such that the nucleation barriers associated with oligomer formation and the subsequent ordering are readily overcome by thermal fluctuations. The height of the nucleation barriers, and the associated lag times depend strongly on the thermodynamic conditions of the system [28].


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

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

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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2572140&req=5

pcbi-1000222-g002: 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.
Mentions: We systematically observed a rapid collapse of the peptides into disordered aggregates that subsequently underwent a structural reorganization and transform into cross-β protofilaments (Figure 1). These results are consistent with a previously described two-step condensation-ordering mechanism [16],[18],[28], which has also been observed experimentally [9]. A plot of the total energy per peptide as a function of the progress variable t (Figure 2) shows that the final structure has a much lower energy than the initial and intermediate states. The major contribution to this energy comes from hydrogen bonding (Figure 2), a result consistent with the recent report that the hydrogen bonding energy provides the dominant factor stabilising the cross-β architecture is represented by hydrogen bonding, while in more disordered states other contributions are also important [31]. The initial state (t<1000), before the hydrophobic collapse, in which all peptides are solvated, has the highest energy and it is unstable. After the hydrophobic collapse has taken place (1000<t<5000), the peptides form a disordered oligomer, which is characterised by similar contributions from hydrophobic interactions and hydrogen bonding (Figure 2); this oligomeric state is lower in energy but metastable with respect to the amyloid state. Finally, with the growth of the cross-β architecture the hydrogen bonding interactions become progressively dominant (Figure 2). The survival time of the disordered oligomeric state is rather short (about 10–15% of the total simulation time) since in order to be able to investigate the self-assembly of the peptides we chose thermodynamic conditions such that the nucleation barriers associated with oligomer formation and the subsequent ordering are readily overcome by thermal fluctuations. The height of the nucleation barriers, and the associated lag times depend strongly on the thermodynamic conditions of the system [28].

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