Molecular insights into Aβ₄₂ protofibril destabilization with a fluorinated compound D744: A molecular dynamics simulation study

The aggregation of amyloid β-peptide (Aβ₄₂ ) into toxic oligomers, fibrils, has been identified as a key process in Alzheimer's disease (AD) progression. The role of halogen-substituted compounds have been highlighted in the disassembly of Aβ protofibril. However, the underlying inhibitory mechanism of Aβ₄₂ protofibril destabilization remains elusive. In this regard, a combined molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of a fluorinated compound, D744, which has been reported previously for potential in vitro and in vivo inhibitory activity against Aβ₄₂ aggregation and reduction in the Aβ-induced cytotoxicity. The molecular docking analysis highlights that D744 binds and interacts with chain A of the protofibril structure with hydrophobic contacts and orthogonal multipolar interaction. MD simulations reveal destabilization of the protofibril structure in the presence of D744 due to the decrease in β-sheet content and a concomitant increase of coil and bend structures, increase in the interchain D23-K28 salt bridge distance, decrease in the number of backbone hydrogen bonds, increase in the average distance between Cα atoms, and decrease in the binding affinity between chains A and B of the protofibril structure. The binding free-energy analysis between D744 and the protofibril structure with Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) reveal that residues Leu17, Val18, Phe19, Phe20, Ala21, Glu22, Asp23, Leu34, Val36, Gly37, and Gly38 of chain A of the protofibril structure contribute maximum towards binding free energy (ΔG_binding  = -44.87 kcal/mol). The insights into the underlying inhibitory mechanism of small molecules that show potential in vitro anti-aggregation activity against Aβ₄₂ will be beneficial for the current and future AD therapeutic studies.