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.