Limits...
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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2572140&req=5

pcbi-1000222-g003: 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.

Mentions: In the example illustrated in Figure 1, the initial stages of the process are characterized by the formation within the disordered oligomer of six small β-sheets that are randomly oriented with respect to each other (Figure 3a). Subsequently, the β-sheets tend to align as their lengths increase, and protofilaments consisting of one, three and four β-sheets are formed (Figure 3b–d). The two major protofilaments observed in this simulation seem to twist around each other (Figure 1, right), resembling the typical behavior observed experimentally [1]. The twisting appears to follow from the growth and alignment of β-sheets, which is a consequence of the tendency to optimize the number of hydrophobic contacts, thereby reducing the interfacial energy [32], and not from the chirality of the peptides, as the latter is not included in the tube model used in this work. As the peptides within the oligomer can move only locally our Monte Carlo dynamics should at least qualitatively resemble their actual dynamics.


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

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

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2572140&req=5

pcbi-1000222-g003: 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.
Mentions: In the example illustrated in Figure 1, the initial stages of the process are characterized by the formation within the disordered oligomer of six small β-sheets that are randomly oriented with respect to each other (Figure 3a). Subsequently, the β-sheets tend to align as their lengths increase, and protofilaments consisting of one, three and four β-sheets are formed (Figure 3b–d). The two major protofilaments observed in this simulation seem to twist around each other (Figure 1, right), resembling the typical behavior observed experimentally [1]. The twisting appears to follow from the growth and alignment of β-sheets, which is a consequence of the tendency to optimize the number of hydrophobic contacts, thereby reducing the interfacial energy [32], and not from the chirality of the peptides, as the latter is not included in the tube model used in this work. As the peptides within the oligomer can move only locally our Monte Carlo dynamics should at least qualitatively resemble their actual dynamics.

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