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

以蛋白质为基础的催化剂，称为酶，对地球上所有的生命都是必不可少的。因此，了解酶是如何进行它们所介导的化学转换的，是基本理解生命的关键。此外，改变酶功能或设计酶功能的能力将在生物技术领域开辟新的途径，如开发新的生物燃料和产生治疗感染和疾病的新药物。要使这些想法成为现实，最重要的是我们对酶作为高效和选择性生物催化剂的作用有一个深入的和基本的了解。为了实现这一目标，最近的研究表明，酶是一种灵活的分子，以一组相互转换的构象状态存在于溶液中，这些构象波动对酶的正常功能至关重要。既然已经确定了这种现象，我们的目标是了解酶的构象灵活性是如何与酶正确发挥作用的能力联系在一起的。为了帮助理解构象柔性如何影响酶的功能，我们将研究酶柔性在依赖GTP的磷酸烯醇式丙酮酸羧基激酶家族中的作用。拟议的工作将集中在人、大鼠和分枝杆菌的同工酶，作为密切和遥远相关的同工酶的代表成员。通过这项研究计划，我们将更好地了解酶功能所需活性部位的构象波动是如何与全球蛋白质运动联系在一起的，以及所有这些耦合运动在单个蛋白质家族的整个进化过程中是如何保守的。这一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，因为有能力选择性和有效地改变酶活性，这是治疗感染和疾病所必需的。

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.