"The role of conformational dynamics in molecular recognition, enzyme function and allostery."

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Protein based catalysts, known as enzymes, are essential to all life on earth. It follows that understanding how enzymes carry out the chemical transformations they mediate is key to a basic understanding of life. In addition, the ability to alter or engineer enzyme function will open up new avenues in biotechnology such as the development of novel biofuels and the generation of new pharmaceuticals to treat infection and disease. For these ideas to become a reality it is of paramount importance that we have an intimate and fundamental understanding of how enzymes function as efficient and selective biological catalysts. Working towards this goal, recent studies have demonstrated that enzymes are flexible molecules and exist in solution as a population of interconverting conformational states and that these conformational fluctuations are vitally important to proper enzyme function. Now that this phenomenon has been identified, it is our goal to understand how this conformational flexibility of enzymes is tied to the ability of the enzyme to function correctly. To help develop this understanding of how conformational flexibility impacts enzyme function, we will investigate the role of enzyme flexibility in the GTP-dependent family of phosphoenolpyruvate carboxykinases. The proposed work will focus upon the isozymes from human, rat and Mycobacterium as representative members of closely and distantly related isozymes. Through this program of research, we will develop a better picture of how conformational fluctuations at the active site, required for enzyme function, are tied to global protein motions as well as how all of these coupled motions are conserved throughout evolution in a single protein family. The immediate benefit of this research program to Canadian society is the continuation of a high-level research training program for graduate and undergraduate students. The long-term impact of this research is a positive impact on the health of all Canadians due to the ability to selectively and potently alter enzyme activity being essential to the treatment of infection and disease.