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 40 and diminish Aβ 40 aggregation. However, the underlying effect of L17A/F19A double mutation on the Aβ 40 structure and dynamics remain elusive. In this regard, the influence of L17A/F19A double mutation on the structure and dynamics of Aβ 40 was investigated using all‐atom molecular dynamics (MD) simulation. MD simulation reveals that mechanism behind modulation of Aβ 40 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 40 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 40 whereas the helical conformation is the most‐populated and energetically favorable conformation in Aβ 40 (L17A/F19A). MD simulation, in accord with the experiment, highlight that L17A/F19A double mutation diminish Aβ 40 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 40 . Overall, MD simulation provides key structural and physical insights into the reduced Aβ 40 aggregation upon L17A/F19A double mutation and an atomic picture of the L17A/F19A‐mediated conformational changes in Aβ 40 .