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

Journal of Chemical Information and Modeling

4 years ago

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

Maryam Heydari Dokoohaki, Amin Reza Zolghadr

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.

Publisher URL: http://dx.doi.org/10.1021/acs.jcim.7b00151

DOI: 10.1021/acs.jcim.7b00151