Unbinding of Abeta peptides from amyloid fibrils: explicit solvent molecular dynamics study

Abstract

We used all-atom molecular dynamics to investigate the unbinding of Alzheimer’s Abeta peptides from amyloid fibrils. The peptide unbinding is driven by temperature-induced structural fluctuations and is thought of as an elementary step in the molecular recycling occurring between fibrillized and soluble Abeta species. Several conclusions can be drawn from our data. Early unbinding stages can be observed on the 100 ns timescale, although complete dissociation is likely to occur on much longer timescale. The unbinding pathway starts with fraying of β-strands from Abeta fibril. We predict that most peptide-fibril interactions will be initially lost by the N-terminal of Abeta peptide. This unbinding scenario can be modified by the specific location of dissociating peptide on the fibril edge. Our simulations provide new molecular details on the process of amyloidogenesis linked to Alzheimer’s disease.