Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aβ₄₀: A molecular dynamics simulation study

Abstract

The aggregation of amyloid-β (Aβ) peptide has been associated with the pathogenesis of Alzheimer disease. The recent studies highlighted that L17A/F19A double mutation increases the structural stability of Aβ and diminish Aβ aggregation. However, the underlying effect of L17A/F19A double mutation on the Aβ structure and dynamics remain elusive. In this regard, the influence of L17A/F19A double mutation on the structure and dynamics of Aβ was investigated using all-atom molecular dynamics (MD) simulation. MD simulation reveals that mechanism behind modulation of Aβ aggregation is associated with a decrease in the β-sheet content and dynamics of the salt bridge D23-K28. The secondary structure analysis highlight more abundant α-helix content in the central hydrophobic core and C-terminal region of Aβ upon L17A/F19A double mutation that is consistent with circular dichroism (CD) results. The free-energy landscape reveal that coil conformation is the most dominant conformation in Aβ whereas the helical conformation is the most-populated and energetically favorable conformation in Aβ (L17A/F19A). MD simulation, in accord with the experiment, highlight that L17A/F19A double mutation diminish Aβ aggregation as the population of the fibril-prone state substantially decreased. The present study, in conjunction with experiment, highlight that L17 and F19 are the critical residues involved in the conformational change that triggers a neurotoxic cascade of Aβ . Overall, MD simulation provides key structural and physical insights into the reduced Aβ aggregation upon L17A/F19A double mutation and an atomic picture of the L17A/F19A-mediated conformational changes in Aβ .

Impact of Mutations on the Conformational Transition from α-Helix to β-Sheet Structures in Arctic-Type Aβ40: Insights from Molecular Dynamics Simulations

“…Our earlier study focused on the effect of L17A/F19A substitution on the wt Aβ 40 , and the results highlighted that the double mutation leads to diminished aggregation tendency of wt Aβ 40 . 35 The sampling of aggregation-prone β-sheet conformation was noted to decrease upon double mutation in both wt Aβ 40 as well as [G22]Aβ 40 . Thus, secondary structure analysis in both studies highlighted that L17 and F19 are the critical residues involved in the conformational changes in wt Aβ 40 and [G22]Aβ 40 .…”

“…The trajectories were examined by utilizing GROMACS tools as used previously in our earlier study. 35 The bending free-energy was evaluated as reported in the previous study. 35 2.3.…”

The F19W mutation reduces the binding affinity of the transmembrane Aβ11–40 trimer to the membrane bilayer

“…Mutations in the Aβ peptide modify its toxicity, assembly, and rate of fibril formation. Specifically, the mutations in the CHC and loop regions, including F19W, 36 F20W, 36 L17A/F19A, 37 Flemish A21G, 38 Dutch E22Q, 39 Italian E22K, 40 Arctic E22G, 41,42 E22Δ, 43 and Iowa D23N 44 could affect the conformational changes in Aβ oligomers. Another example shown that the combination of mutation A2V in N-terminal and histidine tautomerism can affect the Aβ monomer structures and its aggregation process.…”

Exploring the effect of inhibitor AKB‐9778 on VE‐PTP by molecular docking and molecular dynamics simulation

“…Molecular docking is considered as a universal method for predicting the binding affinities between the ligand and the target protein . With the development of molecular docking technology, a great number of new ligands have been discovered and developed accordingly Meanwhile, since the protein simulation was carried out successfully in 1990s, molecular dynamics (MD) simulations have enabled to provide us an understanding on the structure and dynamics of a protein . So far, MD simulation has evolved into a reliable technique to gain insight into the dynamic changes of a system (such as proteins in aqueous solution) for a period of time effectively .…”

“…12 With the development of molecular docking technology, a great number of new ligands have been discovered and developed accordingly 13,14 Meanwhile, since the protein simulation was carried out successfully in 1990s, molecular dynamics (MD) simulations have enabled to provide us an understanding on the structure and dynamics of a protein. [15][16][17] So far, MD simulation has evolved into a reliable technique to gain insight into the dynamic changes of a system (such as proteins in aqueous solution) for a period of time effectively. 18 Therefore, the combination of molecular docking and MD simulation provides an effective method to explore the binding pattern and dynamic behavior of AKB-9778 as VE-PTP inhibitor.…”