Predicting Relative Protein Affinity of Novel Per- and Polyfluoroalkyl Substances (PFASs) by An Efficient Molecular Dynamics Approach

Abstract

With the phasing out of long-chain per- and polyfluoroalkyl substances (PFASs), production of a wide variety of alternative PFASs has increased to meet market demand. However, little is known about the bioaccumulation potential of these replacement compounds. Here, we developed a modeling workflow that combines molecular docking and molecular dynamics simulation techniques to estimate the relative binding affinity of a total of 15 legacy and replacement PFASs for human and rat liver-type fatty acid binding protein (hLFABP and rLFABP). The predicted results were compared with experimental data extracted from three different studies. There was good correlation between predicted free energies of binding and measured binding affinities, with correlation coefficients of 0.97, 0.79, and 0.96, respectively. With respect to replacement PFASs, our results suggest that EEA and ADONA are at least as strongly bound to rLFABP as perfluoroheptanoic acid (PFHpA), and as strongly bound to hLFABP as perfluorooctanoic acid (PFOA). For F-53 and F-53B, both have similar or stronger binding affinities than perfluorooctanesulfonate (PFOS). Given that interactions of PFASs with proteins (e.g., LFABPs) are important determinants of bioaccumulation potential in organisms, these alternatives could be as bioaccumulative as legacy PFASs, and are therefore not necessarily safer alternatives to long-chain PFASs.

Investigation of the Interaction Mechanism of Perfluoroalkyl Carboxylic Acids with Human Serum Albumin by Spectroscopic Methods

“…Moreover, the K a of PFDA-HSA is far higher than that of PFOA-HSA, suggesting that the affinity of PFDA with 10 carbons is higher than that of PFOA with 8 carbons, which is consistent with the results in Figure 1E; this discovery is supported by the fluorescence study conducted by Qin et al [26]. As suggested by Cheng and Ng [34], the relationship between carbon chain length and binding affinity was mainly caused by the van der Waals interaction energy and entropy change during binding, both of which were closely related to carbon chain length. The results in Table 2 indicate as well that the binding constants of PFOA/PFDA to HSA are moderate, suggesting that PFOA/PFDA can be stored and transported in vivo by HSA [35].…”

“…This is in line with the fluorescence research. As described above, the van der Waals interaction energy and entropy change during binding related to carbon chain length could explain this phenomenon [34].…”

Per‐ and Polyfluoroalkyl Substance Toxicity and Human Health Review: Current State of Knowledge and Strategies for Informing Future Research

“…Relatively strong binding with particular proteins (e.g., serum albumin, liver fatty acid binding protein) has already proven useful in correlating PFAS structure with potential for bioaccumulation (Ng and Hungerbühler 2014;Cheng and Ng 2017). Tools including molecular docking and molecular dynamics can correlate relative binding affinities of emerging PFAS with these target proteins and subsequently compare with affinities of legacy chemicals with known bioaccumulation potentials, thus providing a first-tier rapid screening mechanism (Luebker et al 2002;Cheng and Ng 2018). The use of fluorinated substances in pharmaceutical products has led to an unexpected data source for discovery of structural features in PFAS associated with various types of bioactivity.…”

Strategies for grouping per- and polyfluoroalkyl substances (PFAS) to protect human and environmental health

“…Computational methods are based on structure-property relationships and could potentially be used to estimate the bioaccumulation potential of novel and emerging PFAS. For example, the protein affinity of certain legacy and novel PFAS was recently estimated using molecular dynamic approaches, 44 and protein affinity is a key determinant of bioaccumulation potential. Such structure-property relationships may also aid in estimating the elimination half-lives of PFAS, which is another important factor in determining bioaccumulation potential.…”

“…There are clearly relationships between PFAS structural elements and properties and behaviour (e.g. number of uorinated carbons in the peruoroalkyl(ether) chain, protein binding affinities, bioaccumulation potential, elimination rates, bioactivities within the PFAA/peruoroalkylether acid subclasses), 11,44,90,107 but on the other hand, critical toxic endpoints, as well as modes and mechanisms of action vary within the PFAS and such inconsistencies could limit the applicability of QSARs and thus reliability of computational tools.…”