Insights into the Possible Impact of PFAS on Phosphatidylcholine Metabolism and Membranes through Molecular Dynamics Simulations

Abstract

Poly- and perfluoroalkyl substances (PFAS) are pollutants disrupting lipid metabolism and cell membrane integrity with unclear molecular mechanisms. Molecular docking and molecular dynamics (MD) simulations were used to investigate whether the perfluorinated analogue of palmitic acid (PFHxDA, parametrized through SwissParam) could enter membrane lipid metabolism and get embedded in cell membranes, possibly interfering with their properties. The possible role of PFHxDA as substrate for enzymes involved in the biosynthesis of membrane lipids was studied by investigating its interaction with two enzymes belonging to the phosphatidylcholine biosynthetic pathway, Acyl-CoA synthetase 5 and Choline Phosphotransferase 1, through 200 ns MD simulations. PFHxDA and metabolic derivatives displayed binding and dynamic behaviors comparable to native substrates, suggesting they might be either substrates or inhibitors. Concerning membranes, PFHxDA-containing lipids showed altered bilayer observables such as cholesterol packing, area per lipid, membrane thickness, and membrane density during 300 ns MD simulations, possibly affecting membrane fluidity and organization. Although theoretical, these results provide hypothesis-generating yet compelling mechanistic insights into PFAS-mediated disruption of lipid metabolism and membrane integrity, prioritizing specific experimental follow-up.