Insights into the interactions of two perfluorocarboxylic acids with human serum albumin: Thermodynamics, spectroscopy, and molecular simulations

Abstract

The environmental exposure of long-chain perfluorocarboxylic acids (PFCAs) and their potential health hazards, especially their interactions with human serum albumin (HSA), have become a focal point of concern. This study utilized multi-spectroscopy, density functional theory (DFT) calculations, and molecular simulations to explore the interaction mechanisms of perfluorododecanoic acid (PFDoA) and perfluorotetradecanoic acid (PFTeDA) with HSA. The findings revealed that at 298 K, the binding constant of PFDoA with HSA is 4.61 × 10⁵ L/mol, significantly higher than that of PFTeDA at 1.84 × 10³ L/mol, demonstrating a stronger affinity of PFDoA for HSA. Thermodynamic analysis confirmed the binding process to be exothermic, driven primarily by hydrogen bonds and van der Waals forces. Spectroscopic analyses consistently showed that HSA-PFDoA/PFTeDA binding altered the microenvironment of HSA's amino acid residues and induced unwinding of α-helical structures, causing significant conformational changes. Molecular simulations further confirmed that PFDoA and PFTeDA bind to HSA's subdomain IIA, aligning with competitive experimental results. The HSA-PFDoA complex exhibited lower binding energy (-9.5 kcal/mol) and binding free energy (-36.41 kcal/mol) than those of the HSA-PFTeDA complex (-9.1 kcal/mol and -19.69 kcal/mol), suggesting a more stable bond with HSA. Quantum chemical structure analysis highlighted the high reactivity at the carbonyl positions of PFDoA/PFTeDA. This research deepens the comprehension of HSA-PFCA interactions, offering substantial guidance for developing effective strategies to control and prevent PFCA contamination.