The mechanism of growth of fibrils of the β-amyloid peptide (Aβ) was studied by means of a physics-based coarse-grained united-residue (UNRES) model and molecular dynamics (MD) simulations. To identify the mechanism of monomer addition to an Aβ1–40 fibril, an unstructured monomer was placed at a 20 Å distance from a fibril template, and allowed to interact freely with it. The monomer was not biased towards the fibril conformation, by either the force field or the MD algorithm. By using a coarse-grained model with replica exchange MD, a longer time scale was accessible making it possible to observe how the monomers probe different binding modes during their search towards the fibril conformation. Although different assembly pathways were seen, they all follow a dock-lock mechanism, with two distinct locking stages, which is consistent with data from experiments on fibril elongation. Whereas these experiments have not been able to characterize the conformations populating the different stages, we have been able to describe these different stages explicitly by following free monomers as they dock onto a fibril template and adopt the fibril conformation; i.e., we describe fibril elongation step by step, at the molecular level. During the first stage of the assembly, “docking”, the monomer tries different conformations. After docking, the monomer is locked into the fibril through two different locking stages. In the first stage the monomer forms hydrogen bonds with the fibril template along one of the strands in a two-stranded β hairpin; in the second stage, hydrogen bonds are formed along the second strand, locking the monomer into the fibril structure. The data reveal a free-energy barrier separating the two locking stages. The importance of hydrophobic interactions and hydrogen bonds in the stability of the Aβ fibril structure was examined by carrying out additional canonical MD simulations of oligomers with different numbers of chains (4 to 16 chains) with the fibril structure as the initial conformation. The data confirm that the structures are stabilized largely by hydrophobic interactions and show that the intermolecular hydrogen bonds are highly stable and contribute to the stability of the oligomers as well.
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