Collaborative Research: MFB: Ultra-Fast Development of Portable Small Molecule Sensor-Actuators

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In this project, funded by the Molecular Foundation of Biotechnology (MFB) initiative and the Chemical Measurement and Imaging program of the Division of Chemistry, and the Biosensing program of the Division of Chemical, Bioengineering, Environmental, and Transport Systems (CBET), Tim Whitehead of the Department of Chemical and Biological Engineering at the University of Colorado-Boulder, Sean Cutler and Ian Wheeldon at the University of California-Riverside, and Francis Peterson at Medical College of Wisconsin together are developing new ways to control biological systems at will using engineered molecular circuitry. To do this, they will evolve and characterize multiple chemical sensors and derive design rules that enable others to rapidly create new chemically controlled biological responses in any organism of interest. This project seeks to understand how this occurs and define the limits of chemical sensing by specific protein receptors. In doing so, their work will have broad impact on diverse areas of biotechnology, including the precise control of cellular therapies, sensing of illicit drugs or environmental contaminants, and the microbial production of metabolites. This project lies at the interface of chemical biology, organic chemistry, cell and biochemical engineering, and structural biology, and is therefore will provide cross-disciplinary training for the students engaged in this science at all levels. The primary goals of their outreach and education programs are to attract young people to careers in STEM (science, technology, engineering and mathematics) and improve training in chemical biology and industrial biotechnology. The outreach plan involves a multi-pronged effort focused on pre-college and community college engagement, engaging undergraduates through discovery-based labs, and through multiple Research Experiences for Undergraduates programs at all three performance sites.The discovery and exploitation of chemical-induced dimerization (CID) modules was transformative for chemical biology and biotechnology. Chemical-induced dimerization systems have enabled users to construct ligand-controlled systems to modulate cellular and biochemical function, but are constrained by a relatively small number of available protein modules and controlling ligands. This project seeks to develop the foundational knowledge required to understand how CID modules can be reprogrammed to recognize new ligands and to define the limits of chemical space that can be recognized by such systems. To accomplish this, the research team will build and screen computationally designed mutant libraries of PYR1 (PYRABACTIN RESISTANCE 1). PYR1 is a plant hormone receptor that functions through a CID mechanism and possesses a malleable ligand-binding pocket. The project will evolve new PYR1-based sensors controlled by a diverse range of drug-like small molecules. Structural, informatic, and biochemical characterization of these sensors will then be used to develop “rules of recognition” for the PYR1 scaffold and build foundational knowledge required for PYR1-based sensor design. In parallel, a rapid yeast-based system to accelerate PYR1-based sensor development will also be developed. Together, these studies are expected to lead to a detailed understanding of sensor design using the PYR1 system and establish a strong foundation for this enabling and generalizable sensor-design technology.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.