Aggregate geometry in amyloid fibril nucleation

TL;DR

This study introduces a minimal lattice model for peptide self-assembly into amyloid fibrils, revealing that fibril nucleation involves overcoming free-energy barriers related to width expansion, with sigmoidal formation kinetics observed.

Contribution

The paper develops a structure-based lattice model and uses advanced Monte Carlo simulations to elucidate the nucleation mechanism of amyloid fibrils, highlighting the role of aggregate width in free-energy barriers.

Findings

Fibril formation follows sigmoidal kinetics.

Main free-energy barriers are linked to changes in aggregate width.

Reversible aggregate formation observed in simulations.

Abstract

We present and study a minimal structure-based model for the self-assembly of peptides into ordered beta-sheet-rich fibrils. The peptides are represented by unit-length sticks on a cubic lattice and interact by hydrogen bonding and hydrophobicity forces. By Monte Carlo simulations with >100,000 peptides, we show that fibril formation occurs with sigmoidal kinetics in the model. To determine the mechanism of fibril nucleation, we compute the joint distribution in length and width of the aggregates at equilibrium, using an efficient cluster move and flat-histogram techniques. This analysis, based on simulations with 256 peptides in which aggregates form and dissolve reversibly, shows that the main free-energy barriers that a nascent fibril has to overcome are associated with changes in width.