Exploring the Use of Molecular Docking to Identify Bioaccumulative Perfluorinated Alkyl Acids (PFAAs)

Abstract

Methods to predict the bioaccumulation potential of per- and polyfluorinated alkyl substances (PFAS) are sorely needed, given the proliferation of these substances and lack of data on their properties and behavior. Here, we test whether molecular docking, a technique where interactions between proteins and ligands are simulated to predict both bound conformation and interaction affinity, can be used to predict PFAS binding strength and biological half-life. We show that an easy-to-implement docking program, Autodock Vina, can successfully redock perfluorooctanesulfonate (PFOS) to human serum albumin with deviations smaller than 2 Å. Furthermore, predicted binding strengths largely fall within one standard deviation of measured values for perfluorinated alkyl acids (PFAAs). Correlations with half-lives suggest both membrane partitioning and protein interactions are important, and that serum albumin is only one of a number of proteins controlling the fate of these chemicals in organisms. However, few data are available for validation of our approach as a broad screening tool, and available data are highly variable. We therefore call for collection of new data, particularly including proteins other than serum albumin and substances beyond perfluorooctanoic acid (PFOA) and PFOS. The methods we discuss in this work can serve as a framework for guiding such data collection.

Assessing the Ecological Risks of Per‐ and Polyfluoroalkyl Substances: Current State‐of‐the Science and a Proposed Path Forward

“…Uptake of PFAS by exposed organisms and subsequent internal distribution is a function of chemical‐, species‐, and tissue‐specific attributes. For example, some PFAS display a preferential affinity for proteins (e.g., Ng and Hungerbühler 2013, 2014, 2015), which limits the application of models based solely on lipid partitioning to predict bioaccumulation and distribution. Similarly, some PFAS are efficiently metabolized by organisms whereas others are not.…”

Identification, Tissue Distribution, and Bioaccumulation Potential of Cyclic Perfluorinated Sulfonic Acids Isomers in an Airport Impacted Ecosystem

“…Previous studies on branched and linear isomers of PFOS have shown that interactions with serum albumin are affected by the structure of the perfluoroalkyl moiety and that these differences in serum albumin binding affinities are reflected in BAFs. 48 Analogously, it may be hypothesized that the cyclic perfluorocarbon chain results in a weaker interaction with serum albumin for PFECHS and PFPCPeS compared to PFOS which may explain an increased distribution to other tissues than blood and a more rapid elimination. However, additional studies combining in vitro and in silico studies are needed to better understand how different structures of the perfluoroalkyl moiety (linear, branched and cyclic) affect the interaction with different protein classes.…”

PFAS Exposure Pathways for Humans and Wildlife: A Synthesis of Current Knowledge and Key Gaps in Understanding

“…These methods have an advantage of high throughput testing and are not hindered by the lack of available standards and samples. Molecular docking and molecular dynamics are computational approaches originally Accepted Article developed for drug discovery, and are powerful tools for the prediction of protein-ligand interactions.They have now been used to screen a number of legacy and emerging PFAS for binding with serum albumin(Salvalaglio 2010;Ng 2015), L-FABP(Zhang 2013;Ng 2015;Yang 2020), and peroxisome proliferator activated receptors (PPARs), which are thought to be linked to some of the toxic effects of PFAS.…”