Amyloid β Fibril Elongation by Monomers Involves Disorder at the Tip.

The growth of amyloid fibrils from Aβ peptide, one of the key pathogenic players in Alzheimer's disease, is believed to follow a nucleation-elongation mechanism. Fibril elongation is often described as a "dock-lock" procedure, where a disordered monomer adsorbs to an existing fibril in a relatively fast process (docking), followed by a slower conformational transition toward the ordered state of the template (locking). Here, we use molecular dynamics simulations of an ordered pentamer of Aβ42 at fully atomistic resolution, which includes solvent, to characterize the elongation process. We construct a Markov state model from an ensemble of short trajectories generated by an advanced sampling algorithm that efficiently diversifies a subset of the system without any bias forces. This subset corresponds to selected dihedral angles of the peptide chain at the fibril tip favored to be the fast growing one experimentally. From the network model, we extract distinct locking pathways covering time scales in the high microsecond regime. Slow steps are associated with the exchange of hydrophobic contacts, between nonnative and native intermolecular contacts as well as between intra- and intermolecular ones. The N-terminal segments, which are disordered in fibrils and typically considered inert, are able to shield the lateral interfaces of the pentamer. We conclude by discussing our findings in the context of a refined dock-lock model of Aβ fibril elongation, which involves structural disorder for more than one monomer at the growing tip.