Ideas Lab: USPRD: Programmable Small Molecule Biosynthesis

Programmable Small Molecule Biosynthesis This project aims to develop new bioplastics with diverse properties. The team will computationally design complex enzymes within engineered bacteria to produce novel, sturdy bioplastics that can withstand high temperatures and be easily recycled into their original components—or biodegraded and composted if discarded in a landfill. These advances will strengthen supply chain resilience through the bioeconomy and open new directions in domestic manufacturing. Beyond scientific advancements, the initiative will include outreach to undergraduate students to train the next generation of biotechnologists, the development of new workshops on protein design and its real-world applications, and will provide open-source tools for future innovations in biomanufacturing. This interdisciplinary effort seeks to engineer polyketide synthases (PKSs) to produce monomers for polyhydroxyalkanoates (PHAs) with enhanced thermal stability and recyclability. The focus is on creating hybrid PKSs capable of synthesizing gem-dimethylated PHAs (gdPHAs) through advanced computational protein design, addressing the longstanding challenge of slow turnover rates and poor domain interactions in engineered PKSs. Researchers will identify and recombine PKS domains to enable programmable biosynthesis of 3-hydroxyacids with tunable properties, leveraging deep learning-powered design tools. These tools will optimize enzyme functionality, reprogram active sites, and enhance transient protein-protein interactions within PKSs. Experimental design-build-test-learn cycles will validate the designs. Engineered PKSs integrated with PHA synthases will enable bacterial production of PHAs resistant to high temperatures and suitable for depolymerization, allowing either biodegradation or recycling. The project will develop retrosynthesis workflows for PKS pathways, computational tools for protein design, and methodologies for high-GC DNA synthesis. By making these innovations broadly accessible, the work will advance enzyme engineering, support STEM education, and foster domestic biomanufacturing. 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.