CAREER: The Role of Protein Motions in Directing Substrate Conformational Dynamics in Enzyme Catalysis

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Intellectual MeritThe majority of enzymes are protein-based catalysts that are remarkable in terms of their catalytic efficiency and specificity. Enzymes can be considered to be a type of 'nanomachine', and just like every day machines, enzymes have moving parts that are predicted to be important for their function. The main research goal of this project is to understand the relationships between internal protein fluctuations and enzyme catalysis. More specifically, NMR-based methodology will be implemented to rigorously quantify the relationship between the internal motions of the enzyme indole-3-glycerol phosphate synthase and the conformational dynamics of its substrate to provide deeper insight into the role protein motions play in directing the chemical step(s) of enzyme catalysis. Mutational analysis of amino acids predicted to be important in the regulation and coordination of internal protein motions will further reveal how internal protein fluctuations couple to chemically relevant substrate motions. The results for this model enzyme system will be applicable to the basic understanding of protein motion and enzyme catalysis. The results will also provide a more thorough understanding of the design and development of novel enzyme catalysts, such as those used in many industrial processes and products, and can provide further direction to the design of small molecule biomimetic catalysts that take advantage of the basic catalytic principles outlined here. Broader ImpactThe integrated education objectives of this project are to develop, direct and disseminate enzyme-based demonstrations and inquiry-based activities to educate diverse audiences about enzyme technology, and to inspire underrepresented middle and high school students to pursue STEM education and careers, especially in the fields of chemistry and biology. Students will participate through the Higher Achievement Program that brings students from non-college, minority families in the Washington, D.C. area to Penn State, and Penn State Family Science Night that brings science demonstrations and hands-on activities to underserved rural school districts in Pennsylvania. Rural-based teachers (grades 6-12) will be brought to Penn State to participate in enzyme-related demonstrations through the Penn State STEM Teacher Academy. Demonstration and related materials will be made available through Teacher's Domain that is accessed by teachers across the U.S. and in 163 other countries. The ultimate goals of these activities will be to increase participation of underrepresented student populations, enhance educational infrastructure through the creation of digital learning objects, and advance the training and development of middle and high school science teachers.