Study on the Molecular Mechanism of Interaction Between Perfluoroalkyl Acids and PPAR by Molecular Docking

Per- and polyfluoroalkyl substances (PFASs), as a class of "permanent chemicals" with high environmental persistence and bioaccumulation, have attracted much attention. In this study, we focused on the molecular mechanism of the interaction between perfluoroalkyl acids (PFAAs) and peroxisome proliferator-activated receptor δ (PPARδ). Using molecular docking, binding free energy calculation, and structural analysis, we systematically investigated the binding modes, key amino acid residues, and binding energies of 20 structurally diverse PFAAs with PPARδ. The results showed that the binding energies of PFAAs with PPARδ were significantly affected by the molecular weight, the number of hydrogen bond donors, and the melting point of PFAAs. PFAAs with smaller molecular weights and fewer hydrogen bond donors showed stronger binding affinity. The binding sites were concentrated in high-frequency amino acid residues such as TRP-256, ASN-269, and GLY-270, and the interaction forces were dominated by hydrogen and halogen bonds. PFAAs with branched structure of larger molecular weight (e.g., 3m-PFOA, binding energy of -2.92 kcal·mol^-1; 3,3m₂-PFOA, binding energy of -2.45 kcal·mol^-1) had weaker binding energies than their straight-chain counterparts due to spatial site-blocking effect. In addition, validation group experiments further confirmed the regulation law of binding strength by physicochemical properties. In order to verify the binding stability of the key complexes predicted by molecular docking, and to investigate the dynamic behavior under the conditions of solvation and protein flexibility, molecular dynamics simulations were conducted on PFBA, PFOA, 3,3m₂-PFOA, and PFHxA. The results confirmed the dynamic stability of the binding of the high-affinity ligands selected through docking to PPARδ. Moreover, the influence of molecular weight and branched structure on the binding strength was quantitatively verified from the perspectives of energy and RMSD trajectories. The present study revealed the molecular mechanism of PFAAs interfering with metabolic homeostasis through the PPARδ pathway, providing a theoretical basis for assessing its ecological and health risks.