An integrated system for automating ribosome design

Project: Research project

Project Details

Description

The translation apparatus is the cell’s factory for protein biosynthesis, stitching together hundreds or thousands of smaller units called amino acids into sequence defined biopolymers, which are required for the structure, function, and regulation of living systems. The extraordinary synthetic capability of the protein biosynthesis system, which includes the ribosome and the associated factors needed for polymerization, has driven extensive efforts to harness it for societal needs in areas as diverse as energy, materials, and medicine. For example, recombinant protein production has transformed the lives of millions of people through the synthesis of biopharmaceuticals, like insulin, and industrial enzymes, like subtilisin, that are used in laundry detergents. In nature, however, only limited sets of protein monomers are utilized, thereby resulting in limited sets of biopolymers (i.e., proteins). Expanding nature’s repertoire of ribosomal monomers could yield new classes of enzymes, therapeutics, materials, and chemicals with diverse genetically encoded chemistry. For instance, sequence-defined aramids could provide stronger, lighter, sensor-embedded fabrics to improve soldier/police protection. Sequence-defined polypeptides made of protease-resistant monomers (D-, β-amino acids) could lead to antimicrobial drugs that combat rising antibacterial resistance. Such sequence-defined molecules have never been synthesized before.
The Army Research Office recently funded a Department of defense Multidisciplinary University Research Initiative proposal (W911NF-16-1-0372) titled “Engineering the translation apparatus for synthesis of electronically active sequence-defined polymers.” The goal of that proposal is to monitor, interrogate, and understand the process of translation, and with this knowledge diversify, evolve and repurpose the ribosome and its peripheral machinery into an engineered machine to generate non-natural sequence defined polymers polymers as new classes of evolvable matter. A key focus is to develop modified ribosomes that can expand nature’s repertoire of ribosomal monomers to enable alternative (beyond amide and ester) A-B polycondensation reactions in cell-free systems, with an emphasis on electronically active, conjugated sequence defined polymers that fill a ‘sweet spot’ in the size of redox-active species used in solution-based electrochemical energy storage such as flow batteries. Since receiving this funding, we have made several exciting advances in designing and building modified ribosomes. As we have developed new techniques to enable these advances, progress has become limited by the low throughput of designing, building, and testing modified ribosomes. This not only slows progress of our proposed research, but also burdens students, the creative engines of innovative research, with repetitive tasks that keep them from tackling higher level problems. This Defense University Research Instrument Program proposal describes an integrated set of instruments for automating synthesis and functional analysis of modified ribosomes. This system will facilitate and accelerate our ultimate goal of repurposing ribosomes. The impact will be to uniquely enable a broad range of disruptive technologies in advanced personal protective gear, sophisticated electronics, fuel cells, advanced solar cells, and nanofabrication, all topics having significant impact on DoD capabilities. Our work will also expand the definition of biomanufacturing, thereby allowing cell-free biosynthesis to penetrate into new industrial applications and
StatusFinished
Effective start/end date5/24/185/23/19

Funding

  • Army Research Office (W911NF1810181)

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