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

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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.