Intermolecular interactions of perfluoroalkyl acids with human heart-type fatty acid-binding protein

PFAS are widely employed in a broad range of applications, spanning from consumer products, such as non-stick cookware, to industrial processes including semiconductor manufacturing. However, PFAS can accumulate in the human body, and certain compounds have been reported to exhibit carcinogenic potential. Perfluoroalkyl acids (PFAAs), a subclass of PFAS, have been shown to bioaccumulate via interactions with fatty acid-binding proteins (FABPs), although the molecular basis for their recognition remains incompletely elucidated. In this study, fluorescence displacement assays revealed that two perfluoroalkyl acids (PFAAs) showed lower apparent IC₅₀ values for human FABP3 than their corresponding physiological ligands, medium-chain fatty acids (MCFAs). We also determined the ultra-high resolution crystal structures of FABP3 in complex with PFAAs and with MCFAs, thereby providing a molecular basis for PFAAs recognition by FABP3. Structural comparisons demonstrated that PFAAs adopt conformations resembling MCFAs but show distinct solvent-coupled features, including close O···F contacts with ordered water molecules in the binding pocket. Our findings suggest that FABP3 recognizes PFAAs through a mechanism partially shared with fatty acids, but not fully explained by hydrophobic effects alone, with possible additional contributions from dipole-interactive effects. This work provides structural insight into PFAS recognition and suggests a molecular basis by which PFAS could interfere with fatty acid binding to FABPs.