Alzheimer's Disease: Insights into Amyloid Fibril Formation from Lattice Monte Carlo Simulations

Abstract

The neurodegenerative Alzheimer's disease is affecting more than 30 million people worldwide and is linked to the aggregation of the amyloid-β (Aβ) proteins of 40/42 amino acids. Despite extensive experimental studies, the mechanism of formation of amyloid fibrils and plaques is still unclear. To complement experiments, computational studies based on all-atom simulations are very often used. They are however limited in the sampling problem for small systems and short time scales (ns-µs).Our primary aim is to develop a coarse-grained protein lattice model for amyloid proteins. This allows us to determine structures, thermodynamics and dynamics of very large amyloid systems, with the focus on the characterization of oligomers prior to nucleation, and the mechanisms leading to amyloid fibril.After presenting our model and the force field, we show the results of extensive Monte Carlo simulations of oligomers formed by the (Aβ)16-22 and (Aβ)37-42 fragments of the Alzheimer's peptide Aβ. Considering different system sizes, we show that the nucleus size is larger than 10 chains.