Effect of Piedmont mutation (L34V) on the structure, dynamics, and aggregation of Alzheimer's Aβ40 peptide

Publication date: Available online 20 February 2020Source: Journal of Molecular Graphics and ModellingAuthor(s): Rajneet Kaur Saini, Hema Thakur, Bhupesh GoyalAbstractThe 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 Aβ40 aggregation. However, the underlying molecular mechanism of the effect of L34V mutation on Aβ40 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 Aβ40. The secondary structure analysis highlight that L34V mutation enhances Aβ40 self-assembly due to the formation of aggregation-prone β–sheet structure at the C-terminus of Aβ40 monomeric structure. The higher probability of Asp23–Lys28 salt bridge interaction in Aβ40(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 Aβ40, whereas the aggregation-prone β–sheet conformation was observed at the C-terminal region of Aβ40(L34V) in the minimum energy conformations extracted from FEL of Aβ40(L34V). MD simulations, in agreement with experiment, highlight that L34V mutation increases Aβ40 aggre...

Source: Journal of Molecular Graphics and Modelling - February 21, 2020 Category: Molecular Biology Source Type: research