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

以蛋白质为基础的催化剂，也就是酶，对地球上的所有生命都至关重要。由此可见，了解酶是如何进行它们所介导的化学转化的，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，例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，我们对酶如何作为高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。为了实现这一目标，最近的研究表明，酶是灵活的分子，并且在溶液中以相互转换的构象状态的群体存在，这些构象波动对酶的正常功能至关重要。现在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是如何与酶的正常功能联系在一起的。为了帮助理解构象柔韧性如何影响酶的功能，我们将研究酶柔韧性在磷酸烯醇丙酮酸羧激酶gtp依赖家族中的作用。建议的工作将集中在人类，大鼠和分枝杆菌的同工酶作为近亲和远亲同工酶的代表成员。通过这一研究计划，我们将更好地了解酶功能所需的活性位点构象波动如何与整体蛋白质运动相关联，以及所有这些耦合运动如何在整个进化过程中在单个蛋白质家族中保持保守。这个研究项目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项目。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，因为有能力有选择地和有效地改变对治疗感染和疾病至关重要的酶活性。

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.