How Does the P7C3-Series of Neuroprotective Small Molecules Prevent Membrane Disruption?

Molecular dynamics (MD) simulations are conducted to suggest a mechanism of action for the aminopropyl dibromocarbazole derivative (P7C3) small molecule, which protects neurons from apoptotic cell death. At first, the influence of embedded Aβ42 stacks on the structure of membrane is studied. Then, the effect of P7C3 molecules on the Aβ42 fibril enriched membrane and Aβ42 fibril depleted membrane (when Aβ42 fibrils are originally dissolved in the aqueous phase) are evaluated. Also, the formation of an amyloid ion channel in the Aβ42 enriched membrane is examined by calculating deuterium order parameter, density profile, and surface thickness. For Aβ42 in the fully inserted state, ion channel-like structures are formed. The presence of P7C3 molecules in this case just postpones membrane destruction but could not prevent pore formation. In contrast, when both Aβ42 and P7C3 molecules are embedded in the aqueous solution, the P7C3 molecules are self-assembled at membrane/ionic aqueous solution interface and prevent the precipitation and deposition of Aβ42 fibrils into the membrane.