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

基于蛋白质的催化剂，被称为酶，是地球上所有生命所必需的。因此，了解酶如何进行它们介导的化学转化是基本了解生命的关键。此外，改变或改造酶功能的能力将为生物技术开辟新的途径，如开发新型生物燃料和生产治疗感染和疾病的新药。为了使这些想法成为现实，我们对酶如何作为有效和选择性的生物催化剂发挥作用有一个深入和基本的了解是至关重要的。朝着这个目标，最近的研究表明，酶是灵活的分子，并存在于溶液中的相互转换的构象状态的人口，这些构象波动是至关重要的适当的酶功能。既然这种现象已经被确定，我们的目标是了解酶的这种构象灵活性如何与酶正确发挥功能的能力联系在一起。为了帮助发展这种了解构象的灵活性如何影响酶的功能，我们将调查酶的灵活性的作用，在GTP依赖性磷酸烯醇丙酮酸羧激酶家族。拟开展的工作将集中于人、大鼠和分枝杆菌的同工酶，作为近缘和远缘同工酶的代表成员。通过这项研究计划，我们将更好地了解酶功能所需的活性位点的构象波动如何与全局蛋白质运动联系在一起，以及所有这些耦合运动如何在单个蛋白质家族的整个进化过程中保持不变。这项研究计划对加拿大社会的直接好处是继续为研究生和本科生提供高水平的研究培训计划。 这项研究的长期影响是对所有加拿大人的健康产生积极影响，因为选择性和有效地改变酶活性的能力对于治疗感染和疾病至关重要。

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.