International Collaboration In Chemistry: Combined Experimental And Computational Investigations of a Nucleophilic Displacement Reaction With A Hydride Leaving Group

化学国际合作：氢化物离去基团亲核置换反应的实验和计算相结合

• 批准号: 0822536
• 负责人: Willem van der Donk
• 金额: $ 46万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0822536&HistoricalAwards=false
• 关键词: International; Collaboration; Chemistry; Combined; Experimental

Phosphite dehydrogenase catalyzes a chemically unique reaction that so far has eluded a detailed understanding. The enzyme oxidizes phosphite to phosphate in a reaction that has no precedent in chemistry or biology. Although it is not understood in detail how the enzyme achieves catalysis, it is used industrially as an essential helper enzyme (a so-called cofactor regeneration enzyme) for enzymatic production of chemicals that are important for human use. Therefore, a better understanding of the mechanism utilized by the enzyme may help in improving the performance of the protein. In addition, such understanding will provide new insights into how an enzyme can catalyze a chemical reaction that looks improbable and apparently does not take place in the absence of the enzyme. This proposal describes the use of multidisciplinary expertise in the van der Donk laboratory at the University of Illinois and the Mulholland laboratory at the University of Bristol, UK to investigate this highly unusual reaction using both computational and experimental methods. Given the nature of the questions to be addressed and the challenges this system poses, the program requires the development of new methodologies. The development of practically useful computational techniques, and their successful application to complex systems such as enzymes will benefit enormously from a combined experimental and computational approach. In the process of these investigations, new methods will be developed that will be widely applicable for investigations of other biochemical processes. The theoretical developments in the Mulholland group will be driven by the needs of experimental biochemistry, and will be carried out in an integrated, collaborative program. This will include the transfer and development of expertise in the project to other scientists. Experimental testing of predictions in the van der Donk group will challenge and validate the computation techniques (e.g., the effects of enzyme mutations). Furthermore, the collaboration will afford training of computational chemists in the relevant experimental techniques and experimental chemists in state-of-the-art computational methods through continuous exchange of ideas, data, models, methods and personnel between the laboratories. Thus, it is anticipated that this program will produce a cadre of internationally aware young scientists who can communicate effectively across disciplines, and apply and understand the range of techniques that will be at the heart of biochemistry in the future. Undergraduate students from underrepresented minorities will be included in this program and will accompany Dr. van der Donk to the annual SACNAS (Society for the Advancement of Chicanos and Native Americans in Science) meeting to encourage these students to pursue graduate school. Dr. van der Donk is the faculty advisor of a recently established SACNAS chapter at UIUC.This international collaborative research project is supported jointly by NSF and the Engineering and Physical Sciences Research Council (EPSRC) in the United Kingdom. The study is also supported by the Office of International Science and Engineering (OISE) at NSF.

亚磷酸脱氢酶催化一种独特的化学反应，迄今为止尚未得到详细的了解。这种酶将亚磷酸盐氧化成磷酸盐，这种反应在化学或生物学中是史无前例的。尽管尚不清楚这种酶如何实现催化作用，但它在工业上被用作一种重要的辅助酶（所谓的辅因子再生酶），用于酶法生产对人类重要的化学物质。因此，更好地了解酶利用的机制可能有助于提高蛋白质的性能。此外，这种理解将为酶如何催化看似不可能的化学反应提供新的见解，并且在没有酶的情况下显然不会发生。该提案描述了利用伊利诺伊大学范德唐克实验室和英国布里斯托大学穆赫兰实验室的多学科专业知识，利用计算和实验方法研究这种极不寻常的反应。鉴于要解决的问题的性质以及该系统带来的挑战，该计划需要开发新的方法。实用计算技术的发展及其在酶等复杂系统中的成功应用将从实验和计算相结合的方法中受益匪浅。在这些研究过程中，将开发出广泛适用于其他生化过程研究的新方法。穆赫兰小组的理论发展将由实验生物化学的需求驱动，并将在一个综合的、协作的项目中进行。这将包括向其他科学家转让和开发该项目的专业知识。范德唐克小组的预测实验测试将挑战并验证计算技术（例如酶突变的影响）。此外，此次合作还将通过实验室之间不断交流思想、数据、模型、方法和人员，为计算化学家提供相关实验技术方面的培训，并为实验化学家提供最先进计算方法方面的培训。因此，预计该计划将培养一批具有国际意识的年轻科学家，他们能够跨学科有效沟通，并应用和理解未来生物化学核心的一系列技术。来自代表性不足的少数族裔的本科生将被纳入该计划，并将陪同范德唐克博士参加年度 SACNAS（奇卡诺人和美洲原住民科学促进会）会议，以鼓励这些学生攻读研究生。 van der Donk 博士是 UIUC 最近成立的 SACNAS 分会的教职顾问。该国际合作研究项目由 NSF 和英国工程与物理科学研究委员会 (EPSRC) 联合支持。该研究还得到了 NSF 国际科学与工程办公室 (OISE) 的支持。