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Integrative computational approaches to inform relative bioaccumulation potential of per- and polyfluoroalkyl substances (PFAS) across species
Citation:
Cheng, W., J. Doering, C. LaLone, AND C. Ng. Integrative computational approaches to inform relative bioaccumulation potential of per- and polyfluoroalkyl substances (PFAS) across species. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 180(2):212-223, (2021). https://doi.org/10.1093/toxsci/kfab004
Impact/Purpose:
Per and polyfluoroalkyl substances (PFAS) are a group of chemicals that have been widely used in industrial and consumer products and found in the environment. It is known that these substances can bioaccumulate, however there are limited data regarding their ability bioaccumulate across the diversity of species. PFAS are known to interact with certain proteins in mammals thought to be involved in their bioaccumulation potential. Therefore, understanding if these proteins are found in other organisms can provide an initial indication of whether PFAS have the potential to interact with the protein in another species and bioaccumulate. The US EPA Sequence Alignment to Predict Across Species Susceptibility tool (SeqAPASS) was used in this initial study to understand how and if PFAS are likely to interact with the liver fatty acid binding protein in other species to inform follow up cross species bioaccumulation studies. Advanced molecular modeling computational techniques were then used to understand species differences in binding affinity to 9 PFAS.
Description:
The growing necessity of predictive toxicology in chemical safety evaluation has resulted in innovative application and expansion of existing computational methods and the creation of new tools that can address some of the most pressing questions in emerging contaminants research. Of importance is the evaluation of differences in contaminant impacts across species, which can inform both ecosystem protection and the identification of appropriate model species for human toxicity studies. Here we evaluate tools to predict cross-species differences in binding affinity between per- and polyfluoroalkyl substances (PFAS) and the liver fatty acid binding protein (LFABP) which is considered a key determinant of bioaccumulation potential for these ubiquitous environmental contaminants. We focus on two complementary tools: the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool and molecular dynamics (MD). Using human LFABP as the query sequence in SeqAPASS it was determined that the protein was conserved in the majority of vertebrate species, therefore indicating these species would have similar bioaccumulation potential to humans. Level 3 SeqAPASS evaluation was also used to identify potentially destabilizing amino acid differences across species, which were generally supported by DUET stability change predictions. Key differences predicted by SeqAPASS and DUET were selected for further evaluation by molecular dynamics in two ways: by investigating nine single-residue mutations and seven whole-sequence species differences. For the single-point mutations, predicted binding affinities were compared for PFOA and PFNA, and a comparison to a recently published in vitro study was also included as validation. For single residue differences flagged as potentially critical by SeqAPASS, one single point mutation (F50V for PFNA) showed a statistically significant difference with higher affinity than wild-type human L-FABP. MD simulations were then expanded to evaluate binding affinities for 9 different PFAS across 7 species (human, rat, chicken, rainbow trout, zebrafish, Japanese medaka and fathead minnow). Human, rat, chicken and rainbow trout had similar binding affinities to one another for each PFAS, whereas Japanese medaka and fathead minnow had significantly weaker L-FABP binding affinity for some PFAS. In all cases and for all species a strong negative correlation was found between L-FABP binding affinity and chain length. Based on these analyses, the combined use of SeqAPASS and molecular dynamics provides for rapid screening for potential species differences with deeper structural insight. This approach can be easily extended to investigate other important biological receptors and PFAS as potential ligands.
URLs/Downloads:
DOI: Integrative computational approaches to inform relative bioaccumulation potential of per- and polyfluoroalkyl substances (PFAS) across species