Aggregate geometry in amyloid fibril nucleation

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.

4 pages

References in corpus (5)

• An efficient, multiple range random walk algorithm to calculate the density of states
• What drives amyloid molecules to assemble into oligomers and fibrils?
• Self-Templated Nucleation in Peptide and Protein aggregation
• Probing the Mechanisms of Fibril Formation Using Lattice Models
• Phase Diagram of alpha-Helical and beta-Sheet Forming Peptides

Cited by in corpus (12)

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• Universality in the morphology and mechanics of coarsening amyloid fibril networks
• Thermodynamics of amyloid formation and the role of intersheet interactions
• Fragmentation and depolymerization of non-covalently bonded filaments
• The competition between surface adsorption and folding of fibril-forming polypeptides
• The interplay of intrinsic disorder and macromolecular crowding on α-synuclein fibril formation
• Kinetics of fragmentation and dissociation of two-strand protein filaments: Coarse-grained simulations and experiments
• Shape-free theory for the self-assembly kinetics in macromolecular systems
• Intrinsic Defect Formation in Peptide Self-Assembly