Computational And Theoretical Investigations On The Chemistry Of Biocatalysts

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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.