Impact of the mutation A21G (Flemish variant) on Alzheimer's β-amyloid dimers by molecular dynamics simulations

Soluble oligomers of the amyloid beta-protein (A beta) are linked to Alzheimer's disease. Irrespective of the nature of the nucleus before fibril growth, dimers are essential species in A beta assembly, but their transient character has precluded, thus far, high-resolution structure determination. We have investigated the effects of the point mutation A21G on A beta dimers by performing high temperature all-atom molecular dynamics simulations of A beta(40), A beta(42), and their Flemish variants (A21G) starting from their fibrillar conformations. A beta 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 A beta structure and dynamics varies from A beta(40) to A beta(42). Finally, we provide a possible structural explanation for the reduced aggregation rate of A beta fibrils containing the Flemish disease-causing mutation.