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Advancing the SeqAPASS Pipeline from Sequence to Structure to Evaluate Protein Conservation for Species Extrapolation
Citation:
LaLone, C., D. Blatz, S. Vliet, S. Mayasich, C. Simmons, AND T. Transue. Advancing the SeqAPASS Pipeline from Sequence to Structure to Evaluate Protein Conservation for Species Extrapolation. SETAC North America, Fort Worth, TX, November 15 - 19, 2020.
Impact/Purpose:
Technology continues to advance that allows scientists to more rapidly understand complicated biology. There are now computer programs that allow scientists to look at the structure of a chemical and a chemical target found in the body of an organism and rapidly determine whether that chemical has the potential to effect that organism. These computer tools hold great promise in advancing our understanding of whether or not a chemical could interact with a target in multiple species. This understanding could be useful for identifying chemicals that could cause harm to animals or plants in the environment. The US EPA has developed a tool called Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) that helps to understand which organisms might be most susceptible to a given chemical based on how similar the chemical targets are in the body. For hundreds of species that cannot be tested, the SeqAPASS tool provides a yes or no answer to the question of whether or not a particular chemical target exists in another species. However, there is interest in understanding how susceptible one species is compared to another species and being able to provide a quantitative measure of susceptibility across species. Therefore, we have begun to explore and develop a means to make the SeqAPASS predictions more numerical using the computer programs commonly applied to chemical screening in the drug development industry. This presentation will provide the description of how we are applying these methods to many species to screen chemicals.
Description:
Computational methods are needed and being applied to chemical safety evaluations to rapidly make use of all relevant information to make informed decisions for the protection of human and environmental health. In the context of extrapolation of toxicity data/knowledge across species there have been efforts to gather lines of evidence to more thoroughly understand species conservation of biological pathways at the molecular level. Evidence of both structural and functional conservation are key elements that can drive species extrapolation, which is critical when the majority of toxicity testing, which now includes new approach methods in high throughput -screening and -transcriptomics, focus on a limited number of model species, typically mammals. The US Environmental Protection Agency has created a publicly accessible online tool for the evaluation of protein conservation, specifically for the purpose of extrapolating toxicity knowledge across hundreds of species rapidly. The methods and pipeline integrated into the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool continues to evolve as the field of bioinformatics advances, with the objective to make use of all available knowledge regarding a chemical-protein interaction. The development of the tool coincides with streamlining complex analyses with scientifically-based decisions for a streamlined workflow that can be meaningfully applied by both expert and non-expert users. Since its inception in 2016, the SeqAPASS tool has evolved to incorporate three levels of sequence-based comparisons between a protein from a known sensitive species to all other species that have sequence information available yielding predictions of chemical susceptibility. Recent advances in computational biology have allowed for the expansion of the evaluation to compare protein structures across species and predict binding affinity. Taking advantage of state-of-the art tools for creating structural models and comparing similarity of those models has led to a more in-depth understanding of protein conservation and therefore additional lines of evidence for prediction of chemical susceptibility. These advanced methods include the ability to incorporate predicted binding affinity results using molecular docking. Important to advancing such methods for chemical safety assessments is the demonstrated application and ability to define the domain of applicability for these approaches. Therefore, case examples focused on chemical targets, including the liver fatty acid binding protein, will be described to demonstrate how protein structure-based comparisons enhance the understanding of conservation across species in the context of cross species extrapolation.