Effect of Piedmont mutation (L34V) on the structure, dynamics, and aggregation of Alzheimer's Aβ 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 aggregation. However, the underlying molecular mechanism of the effect of L34V mutation on Aβ 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. The secondary structure analysis highlight that L34V mutation enhances Aβ self-assembly due to the formation of aggregation-prone β-sheet structure at the C-terminus of Aβ monomeric structure. The higher probability of Asp23-Lys28 salt bridge interaction in Aβ(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, whereas the aggregation-prone β-sheet conformation was observed at the C-terminal region of Aβ(L34V) in the minimum energy conformations extracted from FEL of Aβ(L34V). MD simulations, in agreement with experiment, highlight that L34V mutation increases Aβ 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.