In Silico Study of Recognition between Aβ40 and Aβ40 Fibril Surfaces: An N-Terminal Helical Recognition Motif and Its Implications for Inhibitor Design.

The recent finding that the surface of amyloid-β (Aβ) fibril can recruit Aβ peptides and convert them into toxic oligomers has rendered fibril surfaces attractive as inhibition targets. Through extensive simulations with hybrid-resolution and all-atom models, we have investigated how Aβ1-40 recognizes its own fibril surfaces. These calculations give a ∼2.6-5.6 μM half-saturation concentration of Aβ on the surface (cf. experimental value ∼6 μM). Aβ was found to preferentially bind to region 16-24 of Aβ40 fibrils through both electrostatic and van der Waals forces. Both terminal regions of Aβ contribute significantly to binding energetics. A helical binding pose of the N-terminal region of Aβ (Aβ3-14) not seen before is highly preferred on the fibril surface. Aβ3-14 in a helical form can arrange side chains with similar properties on the same sides of the helix and maximize complementary interactions with side chain arrays characteristic of amyloid fibrils. Helix formation on a fibril surface implies a helix-mediated mechanism for Aβ oligomerization catalyzed by fibrils. We propose an Aβ3-14 analogue that can exhibit enhanced helical character and interactions with Aβ fibrils and may thus be used as a template with which to pursue potent inhibitors of Aβ-fibril interactions.