Cholesterol-like Condensing Effect of Perfluoroalkyl Substances on a Phospholipid Bilayer

To understand the potential cytotoxicity of perfluoroalkyl substances (PFAS), we study their interactions with a model phospholipid bilayer membrane using molecular dynamics (MD) simulations. Four typical PFAS molecules are investigated, including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctanesulfonic acid (PFOS), and perfluorohexane sulfonate (PFHxS). All of these PFAS molecules are found to spontaneously penetrate the lipid bilayer within a short simulation time (a few nanoseconds). During the penetration process, further free-energy analysis reveals that a PFAS molecule encounters an energy barrier at the bilayer/water interface. To overcome this free-energy barrier, the PFAS molecule flips itself at the interface. We further investigate the influence of embedded PFAS molecules on the membrane properties. All of the embedded PFAS molecules are found to produce a cholesterol-like condensing effect on the lipid bilayer, which includes increases of the order parameters of lipid tails and the thickness of the lipid bilayer and a decrease of area per lipid. Moreover, the PFAS molecules are found to form hydrogen bonds with oxygen atoms at three different positions of a lipid molecule. Our work reveals the penetration pathway of PFAS molecules entering into a lipid bilayer. In addition, the cholesterol-like condensing effect induced by embedded PFAS molecules on model membranes is systematically investigated and discussed. Our simulations can help understand the physical mechanisms of PFAS cytotoxicity.