CDI-Type I: Discovery of Novel Biochemical Pathways

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CBET-0835800BroadbeltCarbon-based compounds are marked for a transition. Chemicals and fuels derived from biomass are viewed as a companion, or even as a successor, to compounds derived from petroleum. Computational thinking is key to begin to move in the direction of biochemical conversion of renewable resources, and to navigate among the vast number of possible combinations of chemicals and processes for producing them. However, it is not sufficient to simply search databases of known compounds and reactions. The diversity of biochemistry suggests that there are pathways that have not been discovered yet, and it is even possible that novel compounds have yet to be synthesized. The PIs will develop a cyber-enabled exploration platform that will discover and analyze complex biochemical reaction networks that:- Present a novel but superior route to a compound that is already produced biochemically- Offer a novel route to produce a compound biochemically that is typically produced via traditional organic synthesis- Propose a biochemical synthesis route to a novel compoundPromising pathways suggested by their computational discovery platform will be tested experimentally by their industrial collaborators.Automated network generation that defines and implements the chemistry of what they have coined "generalized enzyme functions" based on knowledge compiled in existing biochemical databases will be employed. The output is a set of compounds and the pathways connecting them, both known and novel. To identify the most promising of the thousands of different pathways generated, they will link the automated network generation algorithms with property estimation tools. The simplest screening metrics proposed to rank pathways are pathway length and number of known reactions. More sophisticated screening tools that will be developed in the proposed work evaluate kinetic and thermodynamic feasibility. A combination of group additivity estimation, metabolic flux analysis, protein docking analyses, and quantum chemical calculations is proposed.This work has the promise of transforming the way that researchers identify new targets for bioprocessing and provides ripe targets for biochemists who are skilled in protein engineering, allowing them to more efficiently design novel biochemical pathways. The PIs' computational framework offers a new paradigm for the discovery of known and novel compounds and reactions in biochemical systems and includes new methods to identify promising novel pathways that can be implemented practically. Development of the cyber-enabled discovery platform will be carried out in the context of biofuels, but this framework and the guiding principles are applicable to a wide range of different targets for biochemical production, including chemicals and pharmaceuticals. The project will also have a significant impact on the education of high school students, undergraduates and graduate students through outreach activities and research opportunities. The involvement of international and industrial collaborators will enrich the experience of these students through personnel exchange and internship opportunities and expose them to the increasing globalization of research.