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

亚磷酸脱氢酶催化一种独特的化学反应，迄今为止还没有详细的了解。这种酶将亚磷酸盐氧化成磷酸盐的反应在化学或生物学上都没有先例。虽然还不清楚这种酶是如何实现催化作用的，但它在工业上被用作必需的辅助酶（所谓的辅因子再生酶），用于酶促生产对人类使用重要的化学物质。因此，更好地理解酶所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化学反应提供新的见解，这些化学反应看起来不太可能，而且显然在没有酶的情况下不会发生。该提案描述了使用多学科的专业知识，在货车der Donk实验室在伊利诺伊大学和Mulholland实验室在英国的布里斯托大学调查这一非常不寻常的反应，使用计算和实验方法。鉴于要解决的问题的性质和这个系统带来的挑战，该计划需要开发新的方法。实用的计算技术的发展，以及它们在酶等复杂系统中的成功应用，将极大地受益于实验和计算相结合的方法。在这些调查的过程中，将开发新的方法，将广泛适用于其他生物化学过程的调查。在穆赫兰集团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，合作的计划进行。这将包括向其他科学家转让和发展该项目的专门知识。对货车der Donk小组预测的实验测试将挑战和验证计算技术（例如，酶突变的影响）。此外，该合作将通过实验室之间不断交流想法，数据，模型，方法和人员，为计算化学家提供相关实验技术的培训，并为实验化学家提供最先进的计算方法。因此，预计该计划将产生一批具有国际意识的年轻科学家，他们可以跨学科进行有效沟通，并应用和理解未来生物化学核心技术的范围。来自代表性不足的少数民族的本科生将被纳入该计划，并将陪同博士货车der Donk参加年度SACNAS（科学促进奇卡诺人和美洲土著人协会）会议，以鼓励这些学生攻读研究生。货车德·唐克博士是UIUC最近成立的SACNAS分会的指导教师。这个国际合作研究项目由NSF和英国工程与物理科学研究理事会（EPSRC）共同支持。这项研究也得到了NSF国际科学与工程办公室（OISE）的支持。

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.