Per- and polyfluorinated alkyl substances (PFAS) are chemicals that contain multiple carbon-fluorine bonds. Due to their useful oil- and water-repellent properties, PFAS are used in many consumer products, industrial processes, and in firefighting foams. These uses have led to their release to the environment through multiple pathways. The carbon-fluorine bonds in PFAS make them extremely durable, so they do not naturally break down in the environment. Conventional drinking water treatment is not effective at removing most PFAS from water. This is of particular concern because some PFAS are known to cause harm. They can build up in the bodies of humans and wildlife, disrupt normal development, and impair the immune system. Yet no reliable information is available about the properties and health impacts of most PFAS. Recent estimates suggest that more than 4000 different PFAS may have been used and released over time. Detailed toxicity testing data are available for only a handful of these. It is therefore critical that we build our knowledge base regarding the potential impacts of PFAS and identify effective ways of removing them from the environment. The goal of this CAREER proposal is to tackle the enormous challenge posed by PFAS through an innovative complementary approach using predictive modeling and experiments. The results of this study will transform our understanding of PFAS behavior with broad benefits to society through better design of products to reduce environmental impacts at greatly reduced cost. <br/><br/>The objectives of this CAREER proposal are threefold: (1) to use molecular and organism-scale models to conduct large-scale predictive screening of PFAS hazard; (2) to use this new knowledge of structure-interaction relationships to design new bio-inspired sorbents to remove PFAS from water; and (3) to reimagine K-12 and undergraduate education through the use of collaborative model-building in a game-like environment. An experimental, chemical-by-chemical approach to building a comprehensive PFAS knowledge base would be extremely costly in terms of time, laboratory animals, and resources needed. This would delay action in preventing the release of potentially harmful chemicals that could persist indefinitely in the environment without active treatment. By leveraging the power of molecular dynamics to rank the strength of PFAS-biomolecule interactions, coupled to organism-scale physiological models, those PFAS most likely to accumulate in specific tissues or elicit a receptor-specific toxic impact can be rapidly identified. Further, strong interactions with particular biological molecules can be used to design an entirely novel class of selective sorbents. This capitalizes on the very property that makes PFAS hazardous (their tendency to bind to biological macromolecules like proteins) to remove them from water in an efficient and targeted way. Moreover, the broad structural knowledge base that will be created during this CAREER program can be leveraged to 'design out' hazardous properties in future chemicals. Throughout this research program, the power of modeling and simulation will engage and inspire thousands of middle and high school students and their teachers through both formal educational programs and informal STEM outreach, and will be used to enhance systems-level thinking and self-confidence among undergraduates, thereby enhancing the recruitment and retention of diverse cohorts of future STEM leaders.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.