Dissociation of Aβ 16–22 Amyloid Fibrils Probed by Molecular Dynamics

Abstract

The mechanisms of deposition and dissociation are implicated in the assembly of amyloid fibrils. To investigate the kinetics of unbinding of Aβ 16–22 monomers from preformed fibrils, we use molecular dynamics (MD) simulations and the structures for Aβ 16–22 amyloid fibrils. Consistent with experimental studies, the dissociation of Aβ 16–22 peptides involves two main stages, locked and docked, after which peptides unbind. The lifetime of the locked state, in which a peptide retains fibril-like structure and interactions, extends up to 0.5 μs under normal physiological conditions. Upon cooperative rupture of all fibril-like hydrogen bonds (HBs) with the fibril, a peptide enters a docked state. This state is populated by disordered random coil conformations and its lifetime ranges from ∼ 10 to 200 ns. The docked state is stabilized by hydrophobic side chain interactions, while the contribution from HBs is small. Our simulations also suggest that the peptides located on fibril edges may form stable β-strand conformations distinct from the fibril “bulk”. We propose that such edge peptides can act as fibril caps, which impede fibril elongation. Our results indicate that the interactions between unbinding peptides constitute the molecular basis for cooperativity of peptide dissociation. The kinetics of fibril growth is reconstructed from unbinding assuming the reversibility of deposition/dissociation pathways. The relation of in silica dissociation kinetics to experimental observations is discussed.