Binding Affinity and Mechanism of Six PFAS with Human Serum Albumin: Insights from Multi-Spectroscopy, DFT and Molecular Dynamics Approaches

Per- and Polyfluoroalkyl Substances (PFAS) bioaccumulate in the human body, presenting potential health risks and cellular toxicity. Their transport mechanisms and interactions with tissues and the circulatory system require further investigation. This study investigates the interaction mechanisms of six PFAS with Human Serum Albumin (HSA) using multi-spectroscopy, DFT and a molecular dynamics approach. Multi-spectral analysis shows that perfluorononanoic acid (PFNA) has the best binding capabilities with HSA. The order of binding constants (298 K) is as follows: “Perfluorononanoic Acid (PFNA, 7.81 × 106 L·mol−1) > Perfluoro-2,5-dimethyl-3,6-dioxanonanoic Acid (HFPO-TA, 3.70 × 106 L·mol−1) > Perfluorooctanoic Acid (PFOA, 2.27 × 105 L·mol−1) > Perfluoro-3,6,9-trioxadecanoic Acid (PFO3DA, 1.59 × 105 L·mol−1) > Perfluoroheptanoic Acid (PFHpA, 4.53 × 103 L·mol−1) > Dodecafluorosuberic Acid (DFSA, 1.52 × 103 L·mol−1)”. Thermodynamic analysis suggests that PFNA and PFO3DA’s interactions with HSA are exothermic, driven primarily by hydrogen bonds or van der Waals interactions. PFHpA, DFSA, PFOA, and HFPO-TA’s interactions with HSA, on the other hand, are endothermic processes primarily driven by hydrophobic interactions. Competitive probe results show that the main HSA–PFAS binding site is in the HSA structure’s subdomain IIA. These findings are also consistent with the findings of molecular docking. Molecular dynamics simulation (MD) analysis further shows that the lowest binding energy (−38.83 kcal/mol) is fund in the HSA–PFNA complex, indicating that PFNA binds more readily with HSA. Energy decomposition analysis also indicates that van der Waals and electrostatic interactions are the main forces for the HSA–PFAS complexes. Correlation analysis reveals that DFT quantum chemical descriptors related to electrostatic distribution and characteristics like ESP and ALIE are more representative in characterizing HSA–PFAS binding. This study sheds light on the interactions between HSA and PFAS. It guides health risk assessments and control strategies against PFAS, serving as a critical starting point for further public health research.