Acid/Base Effects on Mitigating the Molecular Interactions of Per- and Polyfluoro-Alkyl Substances with Peroxisome Proliferator-Activated Receptor Gamma (PPARG)

Abstract

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. Molecular dynamics (MD) calculations were performed to gain insight 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 was investigated. As the negative effects of PFOS 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, along with the effect of acid/base residues on PPARγ ligand recognition, showed that short, but also long-range interactions allow for PFASs to be competitively replaced from PPARγ. It was also found that, the size of the carbon chain, and hydrogen bonding behavior of PFASs are strong indicators of PFASs/PPARγ binding energy. The study of ligand/residue interactions is of paramount importance for future design of structure-based inhibitors, which can alleviate the effects of PFASs.