Insight into the binding model of per- and polyfluoroalkyl substances to proteins and membranes

Legacy per-and polyfluoroalkyl substances (PFASs) have elicited much concern because of their ubiquitous distribution in the environment and the potential hazards they pose to wildlife and human health. Although an increasing number of effective PFAS alternatives are available in the market, these alternatives bring new challenges. This paper comprehensively reviews how PFASs bind to transport proteins (e.g., serum albumin, liver fatty acid transport proteins and organic acid transporters), nuclear receptors (e.g., peroxisome proliferator activated receptors, thyroid hormone receptors and reproductive hormone receptors) and membranes (e.g., cell membrane and mitochondrial membrane). Briefly, the hydrophobic fluorinated carbon chains of PFASs occupy the binding cavities of the target proteins, and the acid groups of PFASs form hydrogen bonds with amino acid residues. Various structural features of PFAS alternatives such as chlorine atom substitution, oxygen atom insertion and a branched structure, introduce variations in their chain length and hydrophobicity, which potentially change the affinity of PFAS alternatives for endogenous proteins. The toxic effects and mechanisms of action of legacy PFASs can be demonstrated and compared with their alternatives using binding models. In future studies, in vitro experiments and in silico quantitative structure-activity relationship modeling should be better integrated to allow more reliable toxicity predictions for both legacy and alternative PFASs.

Automated summary

Legacy per- and polyfluoroalkyl substances (PFASs) have raised concerns due to their widespread presence in the environment and potential hazards to wildlife and human health. Although there are increasing numbers of effective PFAS alternatives, these alternatives also pose new challenges. This paper reviews how PFASs bind to transport proteins, nuclear receptors, and membranes, and discusses the variations in affinity for endogenous proteins introduced by structural features of PFAS alternatives. The toxic effects and mechanisms of action of legacy PFASs can be compared with their alternatives using binding models, and future studies should integrate in vitro experiments and in silico quantitative structure-activity relationship modeling for better toxicity predictions.