The effect of PFASs on PPAR-gamma/RXR-alpha heterodimer.

Abstract

Nuclear hormone receptors (NRs) are the main protein superfamily that regulates gene expressions in eukaryotic cells. Given the importance of their roles in cells, they become one of the main targets in drug discovery, including thiazolidinediones that act through an NR named peroxisome proliferator-activated receptor gamma (PPAR-gamma). 1 PPAR-gamma can perform as homodimer as well as heterodimer with retinoid X receptor alpha (RXR-alpha) in cells, and the heterodimer is known to impact the regulation of the synthesis of proteins responsible for insulin sensitivity. Per- and polyfluoroalkyl substances (PFASs) are forever chemicals that are being used in numerous industrial applications, including water-repellent coatings, fire-fighting foams, furniture, oil-repellents, and many more. PFAS compounds are very difficult to degrade due to their chemical properties. In recent years, the impact of PFASs on human health as well as on the environment has started to be investigated. Numerous studies show that these compounds disturb many biological systems in humans, including insulin and cholesterol regulation mechanisms, thyroid hormone levels, and so on. It has been shown that PPAR-gamma/RXR-alpha heterodimer is one of the potential targets for PFAS compounds, leading to problems in insulin metabolism. Here, we investigated the effects of selected PFAS compounds on PPAR-gamma/RXR-alpha heterodimer using molecular dynamics simulations and binding free energy calculations. We see that the chain length of PFAS compounds as well as the selection of functional groups impact the binding strength of PFAS compounds. Furthermore, L-carnitine compound, which is shown to have mitigating effects against PFASs, was also investigated.