Binding of Per- and Polyfluoro-alkyl Substances to Peroxisome Proliferator-Activated Receptor Gamma

Peroxisome proliferator receptor gamma (PPARγ), a type II nuclear receptor, fundamental in the regulation of genes, glucose metabolism, and insulin sensitization has been shown to be impacted by per- and poly-fluoroalkyl substances (PFASs). To consider the influence of PFASs upon PPARγ, the molecular interactions of 27 PFASs have been investigated. Two binding sites have been identified on the PPARγ homodimer structure: the dimer pocket and the ligand binding pocket, the former has never been studied prior. Molecular dynamics calculations were performed to gain insights about PFASs-PPARγ binding and the role of acidic and basic residues. The electrostatic interactions for acidic and basic residues far from the binding site were probed, together with their effect on PPARγ recognition. Short-range electrostatic and van der Waals interactions with nearby residues and their influence on binding energies were investigated. As the negative effects of perfluorooctane sulfonate acid were previously shown to be alleviated by one of its natural ligands, l-carnitine, here, the utility of l-carnitine as a possible inhibitor for other PFASs has been considered. A comparison of the binding patterns of l-carnitine and PFASs provides insights toward mitigation strategies for PFASs.