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 Aβ40 and diminish Aβ40 aggregation. However, the underlying effect of L17A/F19A double mutation on the Aβ40 structure and dynamics remain elusive. In this regard, the influence of L17A/F19A double mutation on the structure and dynamics of Aβ40 was investigated using all-atom molecular dynamics (MD) simulation. MD simulation reveals that mechanism behind modulation of Aβ40 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 Aβ40 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 Aβ40 whereas the helical conformation is the most-populated and energetically favorable conformation in Aβ40 (L17A/F19A). MD simulation, in accord with the experiment, highlight that L17A/F19A double mutation diminish Aβ40 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 Aβ40 . Overall, MD simulation provides key structural and physical insights into the reduced Aβ40 aggregation upon L17A/F19A double mutation and an atomic picture of the L17A/F19A-mediated conformational changes in Aβ40 .