Unraveling molecular binding interaction of per-and polyfluoroalkyl substances with human serum albumin: Conformational rearrangement, bioaccumulation potential and toxicokinetic implications

Per- and polyfluoroalkyl substances (PFAS), characterized by environmental persistence and bioaccumulative potential, pose significant risks to human health through biomolecular interactions. This study systematically deciphers the molecular binding interactions of perfluorooctanoic acid (PFOA) and ammonium perfluorooctanoate (APFO) with human serum albumin (HSA) via spectroscopy-based techniques and theoretical molecular docking simulation. Static ground-state complexes were formed spontaneously between PFAS and HSA with moderate binding constants and the stoichiometry of 1:1, driven dominantly by hydrophobic interactions from fluorine-rich perfluoroalkyl chains. Competitive assays and simulations corroborated the involvement of hydrophobic amino acids and localized the binding to Sudlow site I (subdomain IIA), where carboxyl groups were synergized with halogen effects and hydrogen bonds to stabilize complexes. Conformational analysis revealed PFAS-induced structural rearrangements, marked by increased α-helix content and reduced hydrodynamic radius, to improve the hydrophobicity of HSA, suggesting the prolonged PFAS' retention in circulation due to impaired ligand transport functionality. This work establishes a molecular framework linking PFAS-albumin interactions to bioaccumulation pathways, emphasizing the role of fluorine-driven hydrophobicity in toxicokinetics. By integrating multi-spectroscopic and computational approaches, this study provides critical insights for assessing pollutant toxicity at the biomolecular level and underscores the urgency of regulating PFAS exposure to mitigate systemic health risks. • PFAS bind with HSA via fluorine-driven hydrophobic force to form static complexes. • Sudlow site I is identified as the primary HSA binding locus for PFAS. • Binding interaction induces HSA α-helix increase and hydrophobicity improvement. • HSA conformational tightening facilitates the dissemination and retention of PFAS. • Mechanistic framework links fluorine chemistry to bioaccumulation risks.