Amyloid-β fibril disruption by C60-molecular guidance for rational drug design

The WHO has listed Alzheimer's disease among the major neurological disorders with an estimated 35 million people affected worldwide. Amyloid-beta is mostly believed to be the causative factor in Alzheimer's disease and the severity of the disease correlates with the tendency of amyloid-beta to form aggregation patterns-plaques. Lacking effective medication, the identification of any underlying mechanistic principles regarding plaque formation appears to be crucial. Here we carry out computer simulations to study the effect of C-60 on structure and stability of an idealised pentameric construct of amyloid-beta units (a model fibril). A binding site on top of the structurally ordered stack of beta-sheets is identified that triggers structural alterations at the turn region of the hook-like beta-sheet assembly. Significant structural alterations are: (i) the destruction of regular helical twist, (ii) the loss of a stabilizing salt bridge and (iii) the loss of a stabilizing hydrophobic interaction close to the turn. Consequently, the main effect of C-60 is the induction of sizable destabilization in native fibril structure. These structural insights may serve as a molecular guide for further rational drug design of effective inhibitors targeting fibril formation in Alzheimer's disease.