Computational And Theoretical Investigations On The Chemistry Of Biocatalysts

由于要学习重要的基本化学原理及其潜在的健康和商业利益，在原子水平上了解生命是如何运作的至关重要。细胞内的分子通常根据其组成分为几类，其中特别重要的一类生物分子是蛋白质，因为它们是细胞的主力，负责细胞和组织的形状和强度，以及在体内运输氧气等分子。催化蛋白和酶是生命所必需的，因为没有它们，细胞和生物体中的化学过程就不可能以生命可持续的速度发生。***商业催化剂对我们的生活方式至关重要，是织物、食品、石油和天然气以及社会使用和需要的先进材料生产的核心。事实上，90%以上的化学和制药生产都使用它们。然而，许多工业催化剂是非特异性的，能源密集型的，或者要求的反应条件不是环保的。相比之下，酶在相对温和的条件下起作用，例如体温，但具有特殊的反应速率，并且具有高度特异性；它们可以从细胞内的混合物中选择所需的反应物，然后只生成所需的产物。***此外，由于酶在细胞过程中的重要作用，以及某些酶仅存在于某些生物体（如致病细菌）中的事实，酶通常也是治疗药物、抗生素或除草剂的目标。然而，在一些细菌中，目标酶已经进化，降低了当前药物的有效性。事实上，世界卫生组织宣布“抗生素耐药性是对全球健康、粮食安全和发展的最大威胁之一”。理性设计是开发新药来对抗这种快速增长的威胁的有力工具。对于酶靶向药物，这种方法需要对酶催化位点和它们催化的反应的原子水平细节有详细的了解。不幸的是，对于大多数酶来说，这方面的知识往往是有限的。我们的研究使用计算酶学技术，即使用计算机来研究酶，来回答这些重要的问题。更具体地说，我们的目标是了解酶是如何起作用的，它们是如何稳定或控制不稳定或高活性物质的化学反应的，以及催化的基本原理。为了做到这一点，我们将重点放在使用硫的酶上，硫是一种在所有生物体中具有多种重要作用的元素，而古老的酶在蛋白质合成、病毒繁殖和癌症等过程中起着关键作用。我们的发现将造福加拿大和世界，通过发现新的化学，使新的治疗药物和先进材料的发展，以及下一代环境可持续的“智能”催化剂。

Understanding how life works at the atomic level is essential due to the important fundamental chemical principles to be learnt, and its potential health and commercial benefits. Molecules within cells are generally divided into several classes dependent on their composition One particularly important class of biomolecules is proteins as they are the workhorses of cells being responsible, for example, for cell and tissue shape and strength, and transporting of such molecules as oxygen around the body. Catalytic proteins, enzymes, are life-essential as without them chemical processes in cells and organisms could not occur at life-sustainable rates.***Commercial catalysts are essential to our way of life being central to the production of, for example, fabrics, foods, oil and gas, and advanced materials society uses and requires. Indeed, they are used in more than 90% of all chemical and pharmaceutical manufacturing. However, many industrial catalysts are non-specific, energy intensive, or require reaction conditions that are not environmentally green. In contrast, enzymes function under relatively mild conditions, e.g. body temperature, yet have exceptional rates of reaction, and are highly specific; they can select their desired reactants from the mixture within cells and then form only their desired product.***In addition, due to their essential roles in cellular processes, and the fact that some are only found in certain organisms (e.g. disease-causing bacteria), enzymes are often also the target of therapeutic drugs, antibiotics, or herbicides. However, in some bacteria the targeted enzyme(s) have evolved, reducing the effectiveness of current drugs. Indeed, the World Health Organization declared "antibiotic resistance [as] one of the biggest threats to global health, food security, and development". Rational design is a powerful tool for developing new drugs to combat this rapidly growing threat. For enzyme-targeting drugs this approach requires detailed knowledge of the enzyme catalytic site and atomic-level details of the reaction they catalyse. Unfortunately, for most enzymes this knowledge is often at best limited.***Our research uses the techniques of computational enzymology, the use of computers to study enzymes, to answer these important questions. More specifically, we aim to understand how enzymes function, how they stabilize or control the chemistry of unstable or highly reactive species, and the fundamental principles of catalysis. To do this we focus on enzymes that use sulfur, an element with diverse and important roles in all organisms, and ancient enzymes that have key roles in such processes as protein synthesis, viral reproduction, and cancer. Our findings will benefit Canada and the world by discovering new chemistry, enabling the development of new therapeutic drugs and advanced materials, and next-generation environmentally-sustainable 'smart' catalysts.