Perfluorohexane sulfonate (PFHxS) modulates conformational transitions, ligand-binding functions and aggregation of...

Perfluorohexane sulfonate (PFHxS), a persistent short-chain member of perfluoroalkyl substances (PFAS) family, exhibits a long biological half-life and widespread human exposure, raising toxicological concerns. Human serum albumin (HSA), is the most abundant plasma protein, which regulates transport of xenobiotics, including PFAS, and yet the effects of PFHxS binding remain unclear. This study examined PFHxS-HSA interactions across pH-dependent isomeric states using an integrated approach. PFHxS preferentially bound to hydrophobic cavities, particularly Sudlow's site I, via hydrophobic and electrostatic interactions, supported by docking, molecular dynamics, and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) analyses. Spectroscopic data revealed isomer-specific conformational changes, reduced α-helical content, and stabilization of partially unfolded intermediates. At physiological pH, PFHxS displaced diazepam, indicating impaired drug-binding capacity. PFHxS also remodeled the aggregation pathway of HSA, promoting smaller oligomeric species rather than amyloid-like aggregates. Conclusively, PFHxS acts as an active modulator of HSA structure and function, influencing ligand transport, bioavailability, and pharmacokinetics, underscoring potential risks of persistent environmental PFAS exposure to human health.