Effect of Piedmont mutation (L34V) on the structure, dynamics, and aggregation of Alzheimer's Aβ 40 peptide.

The amyloid-β (Aβ) aggregation in the brain has been associated with the development of Alzheimer's disease (AD). The previous studies have reported that Piedmont mutation (L34V) increases the rate of Aβ ₄₀ aggregation. However, the underlying molecular mechanism of the effect of L34V mutation on Aβ ₄₀ structure, dynamics, and aggregation remains largely unclear. In the present study, molecular dynamics (MD) simulations were performed to elucidate the effect of L34V mutation on the structural changes and conformational dynamics of Aβ ₄₀ . The secondary structure analysis highlight that L34V mutation enhances Aβ ₄₀ self-assembly due to the formation of aggregation-prone β-sheet structure at the C-terminus of Aβ ₄₀ monomeric structure. The higher probability of Asp23-Lys28 salt bridge interaction in Aβ ₄₀ (L34V) leads to aggregation prone β-sheet conformations, which has the potential to increase the fibril formation rate. The free energy landscape (FEL) analysis depict a sampling of coil conformation in the free energy minima of Aβ ₄₀ , whereas the aggregation-prone β-sheet conformation was observed at the C-terminal region of Aβ ₄₀ (L34V) in the minimum energy conformations extracted from FEL of Aβ ₄₀ (L34V). MD simulations, in agreement with experiment, highlight that L34V mutation increases Aβ ₄₀ aggregation as the sampling of the aggregation-prone β-sheet conformation substantially increased. Overall, MD simulations provided atomic level details into the increased fibril formation tendency upon L34V mutation and physical insights into the L34V-mediated conformational as well as structural changes in Aβ ₄₀ .
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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