Impact of the Mutation A21G (Flemish Variant) on Alzheimer’s β-Amyloid Dimers by Molecular Dynamics Simulations

Soluble oligomers of the amyloid β-protein (Aβ) are linked to Alzheimer’s disease. Irrespective of the nature of the nucleus before fibril growth, dimers are essential species in Aβ assembly, but their transient character has precluded, thus far, high-resolution structure determination. We have investigated the effects of the point mutation A21G on Aβ dimers by performing high temperature all-atom molecular dynamics simulations of Aβ40, Aβ42, and their Flemish variants (A21G) starting from their fibrillar conformations. Aβ dimers are found in equilibrium between various topologies, and the absence of common structural features shared by the four species makes problematic the design of a unique inhibitor for blocking dimers. We also show that the impact of the point mutation A21G on Aβ structure and dynamics varies from Aβ40 to Aβ42. Finally, we provide a possible structural explanation for the reduced aggregation rate of Aβ fibrils containing the Flemish disease-causing mutation.