Dissociation of Aβ16-22 amyloid fibrils probed by molecular dynamics

The mechanisms of deposition and dissociation are implicated in the assembly of amyloid fibrils. To investigate the kinetics of unbinding of A beta(16-22) monomers from preformed fibrils, we use molecular dynamics (MD) simulations and the structures for A beta(16-22) amyloid fibrils. Consistent with experimental studies, the dissociation of A beta(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 mu s 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 similar to 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 beta-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. (c) 2007 Elsevier Ltd. All rights reserved.