Increasing Amino Acid Diversity in In Vitro Translation with Expanded Genetic Alphabets

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This project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences and the Molecular Genetic Mechanisms Cluster in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences.With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Steven Benner of The Westheimer Institute for Science and Technology (TWIST) within the Foundation for Applied Molecular Evolution to expand the power of biologically created proteins. The next generation of biotechnology will use components of living systems to create unnatural biopolymers, including proteins that contain unnatural amino acids. This award will develop this biotechnology, at the same time as deepening our understanding of how proteins are made in living cells. Proteins produced by biotechnology find use in products as diverse as pharmaceuticals, cosmetics, industrial manufacture, and laundry detergents. Adding unnatural amino acids to these may open up for exploration a horizon of proteins having properties that natural proteins cannot reach. The project trains undergraduate students in methods of cutting-edge technology development.The experiments designed for this project combine chemical synthesis with molecular biology, laboratory evolution, and bioinformatics to gain control over each step in the in vitro synthesis of proteins. This includes developing new ways to put unnatural amino acids onto unnatural transfer RNA molecules by directed evolution of charging catalysts, chemically synthesizing new nucleic acid analogs to manage infidelity in RNA biosynthesis and translation, and understanding of how translation systems exploit auxiliary factors to determine the starting point and ending point of messenger RNA translation. These are coupled with models for the ribosome, recently supported by X-ray crystallography, to build a complex picture of synthetic biology in this space.