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Development and application of efficient and accurate methods for computational enzymology

高效准确的计算酶学方法的开发和应用

基本信息

批准号：
RGPIN-2016-06658
负责人：
Lamoureux, Guillaume
金额：
$ 2.19万
依托单位：
Concordia University
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2016
资助国家：
加拿大
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=616441
关键词：
Development application efficient accurate methods

项目摘要

Computational enzymology is the study of enzymes and enzymatic reactions using computer simulations. It aims primarily at predicting the structure and energy of the short-lived states along an enzymatic reaction, and at connecting them into an atomically-detailed picture. Because these short-lived states are usually not accessible through experimental techniques, computational enzymology can provide new insights into what makes an enzyme work or into how the activity of an enzyme can be enhanced or inhibited. The long-term objectives of our research are to (1) develop methods for computational enzymology that are accurate enough to reveal the mechanism of complex enzymatic reactions, yet efficient enough to simulate the catalytic effects of large-scale protein motion, and (2) use those methods to design new enzymes and new drugs. We are particularly interested in developing computational methods for metalloenzymes, which contain one or many metal cofactors at their reaction sites (zinc, calcium, magnesium, iron, etc.) and are prime targets for medical and industrial applications. Zinc hydrolases, for instance, are involved in numerous biological functions such as blood pressure regulation, tissue repair, and bacterial resistance to antibiotics. Although about half of all known proteins contain at least one metal atom, no method is currently available to efficiently and reliably simulate chemical reactions at metal-binding sites.

计算酶学是利用计算机模拟研究酶和酶反应的学科。它的主要目标是预测酶促反应中沿着的短暂状态的结构和能量，并将它们连接成一个原子级的详细图像。由于这些短暂的状态通常无法通过实验技术获得，因此计算酶学可以为酶的工作原理或酶的活性如何增强或抑制提供新的见解。我们研究的长期目标是（1）开发计算酶学方法，这些方法足够精确，可以揭示复杂酶促反应的机制，但又足够有效，可以模拟大规模蛋白质运动的催化作用，（2）使用这些方法设计新酶和新药。我们对开发金属酶的计算方法特别感兴趣，金属酶在其反应位点含有一个或多个金属辅因子（锌，钙，镁，铁等）。并且是医疗和工业应用的主要目标。例如，锌水解酶参与许多生物功能，如血压调节、组织修复和细菌对抗生素的耐药性。尽管大约一半的已知蛋白质含有至少一个金属原子，但目前还没有方法可以有效可靠地模拟金属结合位点的化学反应。