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The aggregation of amyloid-beta (Aβ) peptides plays a
crucial role in the etiology of Alzheimer’s disease (AD). Recently, it
has been reported that an A2T mutation in Aβ can protect from AD.
Interestingly, an A2V mutation has been also found to offer protection
against AD in the heterozygous state. Structural characterization of
these natural Aβ variants thus offers an intriguing approach to
understand the molecular mechanism of AD. Toward this goal, we have
characterized the conformational landscapes of the intrinsically
disordered WT, A2V, and A2T Aβ1-42 variant monomers and dimers by
using extensive atomistic molecular dynamics (MD) simulations.
Simulations reveal markedly different secondary and tertiary structure
at the central and C-terminal hydrophobic regions of the peptide,
which play a crucial role in Aβ aggregation and related toxicity. For
example, an enhanced double β-hairpin formation was observed in A2V
monomer. In contrast, the A2T mutation enhances disorder of the
conformational ensemble due to formation of atypical long-range
interactions. These structural insights obtained from simulations
allow understanding of the differential aggregation, oligomer
morphology, and LTP inhibition of the variants observed in the
experiments and offer a path toward designing aggregation inhibitors |