Molecular Dynamics Simulation Reveals the Molecular Mechanism of PFAS-induced PPARα Activation.

Per- and polyfluoroalkyl substances (PFAS) could induce hepatotoxicity through the activation of peroxisome proliferator-activated receptor α (PPARα). However, the molecular mechanism of PFAS-induced PPARα activation remains unclear. This study calculated the binding free energy (ΔG_bind) of seven legacy and emerging PFASs with PPARα based on Gaussian accelerated molecular dynamics (GaMD) and molecular mechanics-generalized Born surface area (MM-GBSA). The results indicated a significant correlation (r=0.82, P<0.05) between ΔG_bind and the logarithmic value of half maximal effective concentration (logEC₅₀) of PFAS activating PPARα. Additionally, the number of fluorocarbon atoms positively correlated with ΔG_bind, and PFAS containing carboxyl groups generally had a lower ΔG_bind compared to those containing sulfonate groups. The activation activity of PFAS towards PPARα was found to be directly associated with their binding patterns within the PPARα ligand-binding pocket, as revealed through the analysis of structural stability, hydrogen bond distribution and ligand-residue contacts. PFAS with stronger activities were observed to preferentially bind within the pocket composed of H3, H7, H11 and H12, interacting with key residues such as ILE354, HIS440 and CYS276. These results contribute to the screening of PFAS with PPARα activation effect, and support the evaluation of toxic effects of PFAS. [ABSTRACT FROM AUTHOR]