CDI-Type I: Discovery of Novel Biochemical Pathways

碳基化合物被标记为过渡。从生物质能中提取的化学物质和燃料被视为从石油中提取的化合物的伴侣，甚至是继承者。计算思维是开始向可再生资源的生化转化方向前进的关键，也是在大量可能的化学物质组合和生产它们的过程中导航的关键。然而，仅仅搜索已知化合物和反应的数据库是不够的。生物化学的多样性表明，有些途径尚未被发现，甚至有可能尚未合成新的化合物。pi将开发一个网络探索平台，该平台将发现和分析复杂的生化反应网络：-为已经通过生物化学方式生产的化合物提供一种新颖但优越的途径-提供一种通常通过传统有机合成方式生产的生物化学化合物的新途径-提出一种新化合物的生物化学合成途径他们的计算发现平台提出的有希望的途径将进行实验测试他们的工业合作者。将采用自动化网络生成来定义和实现他们在现有生化数据库中编译的知识基础上创造的“广义酶功能”的化学。输出是一组化合物和连接它们的途径，既有已知的，也有新的。为了确定生成的数千种不同路径中最有希望的路径，他们将把自动网络生成算法与属性估计工具联系起来。最简单的筛选指标提出的排序途径是途径长度和已知反应的数量。更复杂的筛选工具将在拟议的工作中开发，以评估动力学和热力学的可行性。提出了群可加性估计、代谢通量分析、蛋白质对接分析和量子化学计算相结合的方法。这项工作有望改变研究人员识别生物加工新目标的方式，并为擅长蛋白质工程的生物化学家提供成熟的目标，使他们能够更有效地设计新的生化途径。pi的计算框架为在生化系统中发现已知的和新的化合物和反应提供了一个新的范例，并包括新的方法来确定可以实际实施的有前途的新途径。网络发现平台的开发将在生物燃料的背景下进行，但该框架和指导原则适用于生物化学生产的广泛不同目标，包括化学品和药品。该项目还将通过外展活动和研究机会对高中生，本科生和研究生的教育产生重大影响。国际和工业合作伙伴的参与将通过人员交流和实习机会丰富这些学生的经验，并使他们接触到日益全球化的研究。

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.