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

¹ CNRS UPR 9080
² CNRS - UNIVERSITE PARIS 7

^* To whom correspondence should be addressed. E-mail: philippe.derreumaux{at}ibpc.fr.

Submitted on June 8, 2006
Revised on July 3, 2006
Accepted on 19 July 2006

	Abstract

Soluble oligomers of the amyloid -protein (A) are linked to Alzheimer's disease. Irrespective of the nature of the nucleus prior to fibril growth, dimers are essential species in A 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 dimers by performing high temperature all-atom molecular dynamics simulations of A₄₀, A₄₂ and their Flemish variants (A21G) starting from their fibrillar conformations. A 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 an unique inhibitor for blocking dimers. We also show that the impact of the point mutation A21G on A structure and dynamics varies from A₄₀ to A₄₂. Finally, we provide a possible structural explanation for the reduced aggregation rate of A fibrils containing the Flemish disease-causing mutation.

Key Words: A21G mutation, Alzheimer, beta-amyloid, molecular dynamics simulations, oligomers

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