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: $ 5.25万
• 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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748458
• 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.

由于需要学习重要的基本化学原理及其潜在的健康和商业利益，了解生命在原子水平上的运作方式至关重要。细胞内的分子通常根据其组成分为几类。一类特别重要的生物分子是蛋白质，因为它们是细胞的主力，负责细胞和组织的形状和强度，以及将氧气等分子运输到周围身体。催化蛋白质、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无法以生命可持续的速度发生。商业催化剂对于我们的生活方式至关重要，是生产织物、食品、石油和天然气，以及社会使用和需要的先进材料。事实上，它们用于 90% 以上的化学和制药制造。然而，许多工业催化剂是非特异性的、能源密集型的，或者需要不环保的反应条件。相反，酶在相对温和的条件下发挥作用，例如体温，但具有出色的反应速度，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，以及某些仅在某些生物体（例如致病细菌）中发现的事实，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，降低了现有药物的有效性。事实上，世界卫生组织宣称“抗生素耐药性是全球健康、粮食安全和发展的最大威胁之一”。理性设计是开发新药以应对这一快速增长的威胁的强大工具。对于酶靶向药物，这种方法需要详细了解酶催化位点及其催化反应的原子级细节。不幸的是，对于大多数酶来说，这种知识往往是有限的。我们的研究使用计算酶学技术，使用计算机来研究酶，以回答这些重要问题。更具体地说，我们的目标是了解酶如何发挥作用，它们如何稳定或控制不稳定或高活性物质的化学性质，以及催化的基本原理。为此，我们重点关注使用硫的酶，硫是一种在所有生物体中具有多种重要作用的元素，以及在蛋白质合成、病毒繁殖和癌症等过程中发挥关键作用的古老酶。我们的发现将通过发现新化学、促进新治疗药物和先进材料以及下一代环境可持续“智能”催化剂的开发，使加拿大和世界受益。