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

Peroxisome proliferator receptor gamma (PPAR gamma), 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 PPAR gamma, the molecular interactions of 27 PFASs have been investigated. Two binding sites have been identified on the PPAR gamma 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-PPAR gamma 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 PPAR gamma recognition. Short-range electrostatic and van der VVaals 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 futility of Lcarnitine 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.

Automated summary

This study investigates the impact of PFASs on PPAR gamma and their molecular interactions, identifying two binding sites on PPAR gamma and studying the influence of acidic and basic residues on binding. Furthermore, a comparison of the binding patterns of L-carnitine and PFASs provides insights into mitigation strategies for PFASs.