Generic Mechanism of Emergence of Amyloid Protofilaments from Disordered Oligomeric aggregates

TL;DR

This paper proposes a sequence-independent mechanism for amyloid formation, showing how disordered oligomers transition into ordered beta-sheet protofilaments driven by hydrogen bonding and hydrophobic forces, aligning with phase transition principles.

Contribution

It introduces a novel, sequence-independent model explaining amyloid protofilament emergence from disordered oligomers, emphasizing the role of hydrogen bonds and phase transition dynamics.

Findings

Ordered beta-sheets form within oligomers due to hydrogen bonds.

Protofilaments align from initially randomly oriented beta-sheets.

Amyloid aggregation follows Ostwald step rule of phase transitions.

Abstract

The presence of oligomeric aggregates, which is often observed during the process of amyloid formation, has recently attracted much attention since it has been associated with neurodegenerative conditions such as 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 how 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. Initially individual beta-sheets form with random orientations, which subsequently tend to align into protofilaments as their lengths increases. 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.