Molecular Mechanisms of Perfluoroalkyl Substances Integration into Phospholipid Membranes

Understanding the molecular interactions of per- and polyfluoroalkyl substances (PFAS) with phospholipids is crucial for elucidating their pathological mechanisms and developing PFAS remediation strategies. In this study, we employ atomistic molecular dynamics simulations to examine PFAS insertion into phospholipid bilayers, including anionic perfluorooctanesulfonic acid (PFOS), perfluorobutanoic acid (PFBA), perfluorooctanoic acid (PFOA), and perfluorododecanoic acid (PFDoA), as well as neutral polytetrafluoroethylene (PTFE). Our study shows that PFAS insertion into lipid bilayers is driven by the free energy gradient between bulk water and the lipid membrane. Positively charged trimethylammonium groups of phospholipids attract negatively charged PFAS, overcoming the surface hydration barrier. Hydrophobic interactions between PFAS fluoroalkyl tails and lipid chains generate a significant driving force for PFAS reorientation and insertion. The increase in electrostatic potential across the lipid surface aids anionic PFAS insertion, but their dehydration hinders further movement. PFAS insertion enhances membrane ordering and decreases lipid fluidity, potentially affecting cellular functions by modifying membrane rigidity. The extended chain length of PFAS facilitates its interactions with the lipid membrane, resulting in a more pronounced influence on altering its structural and dynamic properties.