Mechanical Unbinding of Aβ Peptides from Amyloid Fibrils

In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: Using the experimental structures of Aβ amyloid fibrils and all-atom molecular dynamics, we study the force-induced unbinding of Aβ peptides from the fibril. We show that the mechanical dissociation of Aβ peptides is highly anisotropic and proceeds via different pathways when force is applied in parallel or perpendicular direction with respect to the fibril axis. The threshold forces associated with lateral unbinding of Aβ peptides exceed those observed during the mechanical dissociation along the fibril axis. In addition, Aβ fibrils are found to be brittle in the lateral direction of unbinding and soft along the fibril axis. Lateral mechanical unbinding and the unbinding along the fibril axis load different types of fibril interactions. Lateral unbinding is primarily determined by the cooperative rupture of fibril backbone hydrogen bonds. The unbinding along the fibril axis largely depends on the interpeptide Lys–Asp electrostatic contacts and the hydrophobic interactions formed by the Aβ C terminal. Due to universality of the amyloid β structure, the anisotropic mechanical dissociation observed for Aβ fibrils is likely to be applicable to other amyloid assemblies. The estimates of equilibrium forces required to dissociate Aβ peptide from the amyloid fibril suggest that these supramolecular structures are mechanically stronger than most protein domains.