Perfluoroalkyl acids interact with major human blood protein fibrinogen: Experimental and computation study

PFAS ( per - and polyfluorinated alkyl substances) are synthetic compounds prized for their stability across various industries, but they pose an increasing threat to the environment and human health. Following the regulation of long-chain PFAS, short-chain and ultra-short-chain molecules have been introduced as substitutes, yet their bioaccumulation potential remains poorly understood. In this study, we combined experimental (intrinsic fluorescence, microscale thermophoresis, clotting assays) and computational approaches to investigate how trifluoroacetic acid, perfluorobutanoic acid, and perfluorooctanoic acid bind to fibrinogen, a key human blood protein. All tested perfluoroalkyl acids (PFAAs) exhibited moderate binding affinity ( K d in the 10 −4 –10 −5 M range), yet circular dichroism and fibrin clot formation assays revealed no functional impairment of fibrinogen. Molecular docking indicated distinct, chain-length-specific binding sites, suggesting multiple routes for PFAAs to interact with fibrinogen without disrupting its primary biological role. These findings challenge the assumption that short-chain PFAS are less bioaccumulative and underscore the need for further research into their long-term health impacts, particularly given their widespread presence in the environment and potential accumulation in human blood. • Ultra-short- and short-chain PFAS also bind human fibrinogen with moderate affinity. • Combined MST and fluorescence confirm distinct PFAS binding sites on fibrinogen. • Fibrinogen function remains unaffected despite PFAS binding in multiple regions. • Molecular docking reveals chain-specific binding sites for TFA, PFBA, PFOA.