%0 Journal Article
%T In Silico Study of Recognition between A¦Â40 and A¦Â40 Fibril Surfaces: An N-Terminal Helical Recognition Motif and Its Implications for Inhibitor Design
%J -
%D 2018
%R https://doi.org/10.1021/acschemneuro.7b00359
%X The recent finding that the surface of amyloid-¦Â (A¦Â) fibril can recruit A¦Â 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 A¦Â1¨C40 recognizes its own fibril surfaces. These calculations give a ¡«2.6¨C5.6 ¦ÌM half-saturation concentration of A¦Â on the surface (cf. experimental value ¡«6 ¦ÌM). A¦Â was found to preferentially bind to region 16¨C24 of A¦Â40 fibrils through both electrostatic and van der Waals forces. Both terminal regions of A¦Â contribute significantly to binding energetics. A helical binding pose of the N-terminal region of A¦Â (A¦Â3¨C14) not seen before is highly preferred on the fibril surface. A¦Â3¨C14 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 A¦Â oligomerization catalyzed by fibrils. We propose an A¦Â3¨C14 analogue that can exhibit enhanced helical character and interactions with A¦Â fibrils and may thus be used as a template with which to pursue potent inhibitors of A¦Â¨Cfibril interactions
%U https://pubs.acs.org/doi/10.1021/acschemneuro.7b00359