Computational And Theoretical Investigations On The Chemistry Of Biocatalysts

生物催化剂化学的计算和理论研究

• 批准号: RGPIN-2018-04840
• 负责人: Gauld, James
• 金额: $ 2.62万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=686552
• 关键词: Computational; Theoretical; Investigations; Chemistry; Biocatalysts

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.

由于要学习的重要基本化学原则及其潜在的健康和商业利益，因此了解生命在原子水平上的工作原理至关重要。细胞中的分子通常分为几个类别，取决于其组成的一类特别重要的生物分子类是蛋白质，因为它们是细胞的主持人，例如细胞和组织形状和强度，以及在身体周围的氧气等分子的运输。催化蛋白，酶是生命的，因为没有它们在细胞和生物体中的化学过程就无法以生命可持续的速度发生。实际上，它们用于所有化学和药物制造中的90％以上。但是，许多工业催化剂是非特异性，能源密集型的，或需要不环保的反应条件。相反，酶在相对温和的条件下的功能，例如体温却具有特殊的反应速率，并且具有很高的特异性；他们可以从细胞内的混合物中选择所需的反应物，然后仅形成所需的产物。***此外，由于它们在细胞过程中的重要作用，并且仅在某些生物体（例如引起疾病的细菌）中发现了某些人，因此酶通常也是治疗药物，抗生素或雌雄同体的靶标。然而，在某些细菌中，靶向酶已经发展，从而降低了当前药物的有效性。的确，世界卫生组织宣布“抗生素抗性（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应对这种快速增长的威胁的强大工具。对于靶向酶的药物，这种方法需要详细了解它们催化的反应的酶催化位点和原子水平的细节。不幸的是，对于大多数酶而言，这种知识通常是最多有限的。更具体地说，我们旨在了解酶如何稳定或控制不稳定或高度反应性物种的化学以及催化的基本原理。为此，我们专注于使用硫，在所有生物体中具有多种和重要作用的元素以及在蛋白质合成，病毒繁殖和癌症等过程中具有关键作用的古代酶。我们的发现将通过发现新的化学，使新的治疗药物和先进材料的开发以及下一代环境可持续的“智能”催化剂来使加拿大和世界受益。