Binding of Per- and Polyfluoroalkyl Substances (PFAS) to the PPAR/RXR-DNA Complex

Nuclear receptors are the fundamental building blocks of gene expression regulation and the focus of many drug targets. While binding to DNA, nuclear receptors act as transcription factors, governing a multitude of functions in the human body. Peroxisome proliferator-activator receptor gamma (PPAR gamma) and the retinoid X receptor alpha (RXR alpha) form heterodimers with unique properties and have a primordial role in insulin sensitization. This PPAR gamma/RXR alpha heterodimer has been shown to be impacted by per- and polyfluoroalkyl substances (PFAS) and linked to a variety of significant health conditions in humans. Herein, a selection of the most common PFAS (legacy and emerging) was studied utilizing molecular dynamics simulations for PPAR gamma/RXR alpha. The local and global structural effects of PFAS binding on the known ligand binding pockets of PPAR gamma and RXR alpha as well as the DNA binding domain (DBD) of RXR alpha were inspected. The binding free energies were predicted computationally and were compared between the different binding pockets. In addition, two electronic structure approaches were utilized to model the interaction of PFAS within the DNA binding domain, density functional theory (DFT) and domain-based pair natural orbital coupled cluster with perturbative triples (DLPNO-CCSD(T)) approaches, with implicit solvation. Residue decomposition and hydrogen-bonding analysis were also performed, detailing the role of prominent residues in molecular recognition. The role of l-carnitine is explored as a potential in vivo remediation strategy for PFAS interaction with the PPAR gamma/RXR alpha heterodimer. In this work, it was found that PFAS can bind and act as agonists for all of the investigated pockets. For the first time in the literature, PFAS are postulated to bind to the DNA binding domain in a nonspecific manner. In addition, for the PPAR gamma ligand binding domain, l-carnitine shows promise in replacing smaller PFAS from the pocket.