Development and application of efficient and accurate methods for computational enzymology

计算酶学是利用计算机模拟来研究酶和酶反应的学科。它的主要目的是预测沿着酶反应的短暂状态的结构和能量，并将它们连接成原子细节的图像。由于这些短暂的状态通常不能通过实验技术获得，计算酶学可以为酶的工作原理或酶的活性如何被增强或抑制提供新的见解。*我们研究的长期目标是(1)开发计算酶学的方法，这些方法足够准确地揭示复杂的酶反应的机制，并且足够有效地模拟大规模蛋白质运动的催化效应，以及(2)使用这些方法来设计新的酶和新的药物。*我们特别感兴趣的是开发金属酶的计算方法，它的反应部位包含一个或多个金属辅因子(锌，钙、镁、铁等)是医疗和工业应用的主要目标。例如，锌水解酶参与了许多生物学功能，如调节血压、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，但目前还没有有效和可靠的方法来模拟金属结合部位的化学反应。

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.**