Exploring the Use of Molecular Docking to Identify Bioaccumulative Perfluorinated Alkyl Acids (PFAAs) (original) (raw)
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Perfluorooctanoic acid (PFOA) is a toxic compound that is absorbed and distributed throughout the body by noncovalent binding to serum proteins such as human serum albumin (hSA). Though the interaction between PFOA and hSA has been already assessed using various analytical techniques, a high resolution and detailed analysis of the binding mode is still lacking. We report here the crystal structure of hSA in complex with PFOA and a medium-chain saturated fatty acid (FA). A total of eight distinct binding sites, four occupied by PFOAs and four by FAs, have been identified. In solution binding studies confirmed the 4:1 PFOA-hSA stoichiometry and revealed the presence of one high and three low affinity binding sites. Competition experiments with known hSA-binding drugs allowed locating the high affinity binding site in subdomain IIIA. The elucidation of the molecular basis of the interaction between PFOA and hSA might provide not only a better assessment of the absorption and elimination mechanisms of these compounds in vivo but also have implications for the development of novel molecular receptors for diagnostic and biotechnological applications. K E Y W O R D S binding mode, crystal structure, fluoroalkyl substances, human serum albumin, molecular interaction, perfluorooctanoic acid 1 | INTRODUCTION Perfluorooctanoic acid (PFOA) is a perfluoroalkyl substance (PFAS) with a carboxyl functional group and seven fluorinated carbon atoms. 1 PFOA is a man-made
Environmental science & technology, 2018
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...
Interaction of perfluorooctanoic acid with human serum albumin
BMC Structural Biology, 2009
Recently, perfluorooctanoic acid (PFOA) has become a significant issue in many aspects of environmental ecology, toxicology, pathology and life sciences because it may have serious effects on the endocrine, immune and nervous systems and can lead to embryonic deformities and other diseases. Human serum albumin (HSA) is the major protein component of blood plasma and is called a multifunctional plasma carrier protein because of its ability to bind an unusually broad spectrum of ligands.
Toxics
The biological impacts of per- and polyfluorinated alkyl substances (PFAS) are linked to their protein interactions. Existing research has largely focused on serum albumin and liver fatty acid binding protein, and binding affinities determined with a variety of methods show high variability. Moreover, few data exist for short-chain PFAS, though their prevalence in the environment is increasing. We used molecular dynamics (MD) to screen PFAS binding to liver and intestinal fatty acid binding proteins (L- and I-FABPs) and peroxisome proliferator activated nuclear receptors (PPAR-α, -δ and -γ) with six perfluoroalkyl carboxylates (PFCAs) and three perfluoroalkyl sulfonates (PFSAs). Equilibrium dissociation constants, KDs, were experimentally determined via equilibrium dialysis (EqD) with liquid chromatography tandem mass spectrometry for protein-PFAS pairs. A comparison was made between KDs derived from EqD, both here and in literature, and other in vitro approaches (e.g., fluorescence...
Journal of Agricultural and Food Chemistry, 2010
Perfluoroalkyl acids (PFAAs), an emerging class of globally environmental contaminants, pose a great threat to humans with wide exposure from food and other potential sources. To evaluate the toxicity of PFAAs at the protein level, the effects of three PFAAs on bovine serum albumin (BSA) were characterized by fluorescence spectroscopy, synchronous fluorescence spectroscopy, and circular dichroism (CD). On the basis of the fluorescence spectra and CD data, we concluded that perfluoropentanoic acid (PFPA) had little effect on BSA. However, perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) exhibited remarkable fluorescence quenching, which was attributed to the formation of a moderately strong complex. The enthalpy change (ΔH) and entropy change (ΔS) indicated that van der Waals forces and hydrogen bonds were the dominant intermolecular forces in the binding of PFAAs to BSA. Furthermore, the BSA conformation was slightly altered in the presence of PFOA and PFDA, with a reduction of R helix. These results indicated that PFAAs indeed impact the conformation of BSA, and PFAAs with longer carbon chains were more toxic, especially at lower concentrations.
Bioconcentration of Perfluorinated Alkyl Acids: How Important Is Specific Binding?
Environmental Science & Technology, 2013
Perfluorinated alkyl acids (PFAAs) are important global pollutants with unique pharmacokinetics. Evidence is accumulating that their behavior within organisms is affected by interaction with a number of proteins. In mammals, serum albumin, fatty acid binding proteins (FABPs) and organic anion transporters (OATs) have been identified as important to the tissue distribution, species-specific accumulation, and species-and genderspecific elimination rates of perfluoroalkyl carboxylates and perfluoroalkane sulfonates. Similar pharmacokinetics has been identified in fish. Yet, no mechanistic model exists for the bioaccumulation of PFAAs in fish that explicitly considers protein interactions. In this work, we present the first mechanistic protein-binding bioconcentration model for PFAAs in fish. Our model considers PFAA uptake via passive diffusion at the gills, association with serum albumin in the circulatory and extracellular spaces, association with FABP in the liver, and renal elimination and reabsorption facilitated by OAT proteins. The model is evaluated using measured bioconcentration and tissue distribution data collected in two previous studies of rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio). Comparing our model with previous attempts to describe PFAA bioconcentration using a nonspecific (partitioning-type) approach shows that inclusion of protein interactions is key to accurately predicting tissue-specific PFAA distribution and bioconcentration.
Environmental Toxicology and Chemistry, 2010
Perfluorocarboxylic acids (PFCAs) of chain length greater than seven carbon atoms bioconcentrate in the livers of fish. However, a mechanistic cause for the empirically observed increase in the bioconcentration potential of PFCAs as a function of chain length has yet to be determined. To this end, recombinant rat liver fatty acid-binding protein (L-FABP) was purified, and its interaction with PFCAs was characterized in an aqueous system at pH 7.4. Relative binding affinities of L-FABP with PFCAs of carbon chain lengths of five to nine were established fluorimetrically. The energetics, mechanism, and stoichiometry of the interaction of perfluorooctanoic acid (PFOA) with L-FABP were examined further by isothermal titration calorimetry (ITC) and electrospray ionization combined with tandem mass spectrometry (ESI-MS/MS). Perfluorooctanoic acid was shown to bind to L-FABP with an affinity approximately an order of magnitude less than the natural ligand, oleic acid, and to have at least 3:1 PFOA:L-FABP stoichiometry. Two distinct modes of PFOA binding to L-FABP were observed by ESI-MS/MS analysis; in both cases, PFOA binds solely as the neutral species under typical physiological pH and aqueous concentrations of the anion. A comparison of their chemical and physical properties with other well-studied biologically relevant chemicals showed that accumulation of PFCAs in proteins as the neutral species is predictable. For example, the interaction of PFOA with L-FABP is almost identical to that of the acidic ionizing drugs ketolac, ibuprofen, and warfarin that show specificity to protein partitioning with a magnitude that is proportional to the K OW (octanol-water partitioning) of the neutral species. The experimental results suggest that routine pharmacochemical models may be applicable to predicting the protein-based bioaccumulation of long-chain PFCAs.
Chemosphere, 2017
Exposure to perfluorinated and polyfluoroalkyl substances (PFCs/PFASs), endocrine disrupting halogenated pollutants, has been linked to various diseases including thyroid toxicity in human populations across the globe. PFASs can compete with thyroxine (T4) for binding to the human thyroid hormone transport protein transthyretin (TTR) which may lead to reduce thyroid hormone levels leading to endocrine disrupting adverse effects. Environmental fate and endocrine-disrupting activity of PFASs has initiated several research projects, but the amount of experimental data available for these pollutants is limited. In this study, experimental data for T4-TTR competing potency of 24 PFASs obtained in a radioligand-binding assay were modeled using classification- and regression-based quantitative structure-activity relationship (QSAR) tools with simple molecular descriptors obtained from chemical structure of these compounds in order to identify the responsible structural features and fragmen...
Binding of Perfluorinated Fatty Acids to Serum Proteins
Environmental Toxicology and Chemistry, 2003
Perfluorooctane sulfonic acid (PFOS) accumulates in the liver and blood of exposed organisms. The potential for these surfactant molecules to interfere with hormone/protein interactions in blood is of concern given the importance of these interactions. The PFOS binding to serum proteins was investigated by assessing its ability to displace a variety of steroid hormones from specific binding proteins in the serum of birds and fishes. Perfluorooctane sulfonic acid had only a weak ability to displace estrogen or testosterone from carp serum steroid binding proteins. Displacement of cortisone in avian sera occurred at relatively low PFOS concentrations. Corticosterone displacement potency increased with chain length, and sulfonic acids were more potent than carboxylic acids. The PFOS concentrations estimated to cause these effects were 320 M or greater, equivalent to serum concentrations greater than 160 mg/L. Using mass spectrometry and direct in vitro binding assays, PFOS was demonstrated to bind strongly to bovine serum albumin (BSA) in a 1:1 stoichiometric ratio. It appears that PFOS in serum is in general bound to albumins. Concentrations of PFOS required to saturate albumin would be in excess of 50 to 100 mg/L. Based on current environmental concentrations, it is unlikely that PFOS would cause displacement of hormones from serum proteins in wildlife.