Anion Exchange Mechanism of PFAS with Cholestyramine: Implications for PFAS Removal from the Human Body

Per- and polyfluoroalkyl substances (PFAS) can bioaccumulate and may increase the risk of cancer development. Clinical studies report that cholestyramine treatment lowers serum PFAS concentrations, but the molecular energetics, interactions and underlying mechanisms of PFAS exchange with the resin remain incompletely understood. Here, we present a quantum perspective to define the mechanism of PFAS anion exchange with cholestyramine. Quantum chemistry calculations, including density functional theory (DFT), were used to evaluate chloride exchange for perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA), and 6:2 fluorotelomer carboxylic acid (6:2 FTCA) at an isolated ammonium site and in an extended styrene-divinylbenzene model. Single-site ion pairing did not make exchange with chloride thermodynamically favorable. Adding the divinylbenzene backbone lowered electronic exchange energies for all four PFAS, whereas the Gibbs free-energy effect varied among compounds. Energy decomposition analysis showed that electrostatic attraction was the largest stabilizing contribution, while added backbone contacts altered dispersion, exchange correlation and Pauli contributions. For PFOA, changing the bound state continuum from water to 1-octanol produced little net change in exchange free energy. Three separately seeded 10 ns molecular dynamics trajectories of a hydrated pVBTMA12 oligomer showed persistent PFOA contact with changing headgroup and tail environments, although global structural convergence was not established. Together, these results support a molecular mechanism in which electrostatic ion pairing and PFAS backbone contacts jointly influence anion exchange favorability in simplified cholestyramine models. This mechanistic framework provides testable hypotheses for PFAS sequestration and identifies aromatic contact area and ammonium site geometry as design variables for future resin optimization. These findings connect quantum level interaction energetics with experimentally testable strategies for developing improved PFAS sequestrants. Computational data and code are archived in Zenodo, and a web-based graphical user interface tool is available online.