The Control of Non-Chemical Steps in Enzyme Catalysis

酶控制着几乎所有生命化学反应的发生速度。它们也是治疗干预、工业生物技术和合成生物学的核心，在这些领域，生物学正以全新的方式得到利用。酶活性的操纵是这些研究领域的一个关键因素。因此，了解是什么决定了酶的活性是当务之急。酶的活性已经被研究了几十年，但它们如何工作的重要方面还没有科学的方法。最近，人们开发了一些工具，可以在几乎每个原子的分辨率上检查酶，告诉我们它们的性质，它们是如何相互作用的，它们是如何运动的。这为研究酶在其反应周期的不同阶段的行为提供了比迄今为止更详细的机会。正确理解所有这些元素及其相互作用对于操纵酶活性至关重要。在这项研究中，我们将解决三个问题。首先，我们将研究为什么酶中特定位置的某些氨基酸在各种不同的生物体中都是相同的，然而，根据目前的模型，在酶的工作中没有作用。其次，我们将研究当两种蛋白质相互作用时，酶是否会使用一些技巧来确保相互作用是特异性的，但既不强也不持久。第三，我们将研究在某些酶处于静止阶段时发现的一种行为是否特别存在，以确保酶的整个种群在条件合适的情况下不会过于活跃。这种情况发生在酶做多项工作的时候，太快完成其中一项工作是有害的。这项研究的总体背景是开发更好的预测模型，以提高酶在治疗、工业生物技术和合成生物学方面的利用。

Enzymes control the rate at which almost all chemistry of life occurs. They are also at the core of therapeutic intervention, industrial biotechnology, and synthetic biology, where biology is being utilised in entirely new ways. The manipulation of enzyme activity is a key element in each of these areas of research. Hence, understanding what determines the activity of enzymes is a high priority. Enzyme activity has been studied for many decades but important aspects of how they work have eluded the scientific approaches available at the time. Very recently, tools have been developed that allow the examination of enzymes at the resolution of almost every individual atom, telling us about their properties, how they interact and how they move. This opens up the opportunity to examine in far greater detail than has been possible to-date how enzymes behave at different stages of their reaction cycles. A proper understanding of all of these elements and their interplay is crucial to manipulating enzyme activity. In this study we will address three questions. Firstly we will examine why certain amino acids at specific positions in enzymes are the same in a wide variety of different organisms and yet, according to current models, have no role in how the enzymes work. Secondly, we will examine whether enzymes use tricks that sometimes occur when two proteins interact that make sure that the interaction is specific but neither strong nor long lasting. Thirdly, we will examine whether a behaviour found in some enzymes when they are in a resting phase are specifically present to ensure that the whole population of an enzyme is not too active unless the conditions are right. This scenario occurs when an enzyme does more than one job, and it is detrimental to be too fast doing one of the jobs. The overall context of the study is to develop better predictive models that improve the utilization of enzymes in therapeutic, industrial biotechnology and synthetic biology settings.