The role of conformationally plastic loops in enzyme function, stability and regulation

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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 family of enzymes identified as phosphoenolpyruvate carboxykinases. Through this program of research, we will develop a better picture of how conformational transitions in loop elements that are part of the enzyme's structure are necessary for catalytic function, enzyme stability, and regulation of activity as well as investigate the structural constraints on mobile elements of protein structure through analysis of enzymes in this family from diverse species.