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

Laboratoire de Biochimie Théorique, UPR 9080, Centre National de la Recherche Scientifique, Institut de Biologie Physico-Chimique, et Université Paris, Paris, France

Correspondence: Address reprint requests to P. Derreumaux, Tel.: 33-1-58-41-50-16; E-mail: philippe.derreumaux{at}ibpc.fr.

Soluble oligomers of the amyloid ß-protein (Aß) are linked to Alzheimer's disease. Irrespective of the nature of the nucleus before fibril growth, dimers are essential species in Aß assembly, but their transient character has precluded, thus far, high-resolution structure determination. We have investigated the effects of the point mutation A21G on Aß dimers by performing high temperature all-atom molecular dynamics simulations of Aß₄₀, Aß₄₂, and their Flemish variants (A21G) starting from their fibrillar conformations. Aß 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 Aß structure and dynamics varies from Aß₄₀ to Aß₄₂. Finally, we provide a possible structural explanation for the reduced aggregation rate of Aß fibrils containing the Flemish disease-causing mutation.

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