Development and application of efficient and accurate methods for computational enzymology

我们正在开发一个计算酶学的研究项目。计算酶学是利用计算机模拟研究酶及其催化的生化反应。目前，模拟酶反应的唯一方法是足够准确地揭示酶的机制，需要在超级计算机上进行数周甚至数月的计算。我们的长期目标是开发新的方法，允许在几个小时内进行相同的模拟，并使计算研究在更大的规模。我们目前的重点是金属酶，这是一种蛋白质，通过结合锌、铁或镁等金属原子来获得其生化活性。金属酶参与呼吸、消化、组织生长和血压调节等多种生物学功能，是主要的治疗靶点。一些金属酶抑制剂是治疗高血压、艾滋病和癌症的有效药物。为了开发这些新方法，我们首先尽可能准确地模拟在给定金属酶中观察到的所有可能的化学反应的“剥离”版本。然后，一劳永逸地生成的结果数据用数学公式表示，这些数学公式足够逼真地模拟其属性，可以用作原始模拟的替代品。然后，这些公式被用来模拟化学反应的“装扮”版本，并研究任何具有与原型相同的一般结构的酶的功能。我们有兴趣回答以下问题：为什么一种金属酶与某种金属结合时比与另一种金属结合时更活跃？在酶的活性部位含有一个以上的金属原子，每个金属原子的作用是什么？酶的哪些运动对其活性很重要？这些运动可以用小分子来抑制吗？在短期内，我们的工作将有助于了解许多催化机制的分子细节。从长远来看，它将有助于从三维结构中解码酶的功能，开发新的抑制剂，并减少现有抑制剂的副作用。

We are developing a research program in computational enzymology. Computational enzymology is the study of enzymes and the biochemical reactions they catalyze using computer simulations. At present time, the only methods for simulating enzymatic reactions that are sufficiently accurate to reveal the mechanism of an enzyme require weeks, if not months of calculation on a supercomputer. Our long-term objective is to develop new methods that allow the same simulations to be performed in a few hours, and that enable computational studies at a much larger scale. Our current focus is on metalloenzymes, which are proteins that get their biochemical activity from binding a metal atom such as zinc, iron, or magnesium. Metalloenzymes are involved in numerous biological functions such as respiration, digestion, tissue growth, and blood-pressure regulation, and are prime therapeutic targets. Some metalloenzyme inhibitors are efficient drugs against hypertension, HIV/AIDS, and cancer. To develop these new methods, we first simulate--as accurately as possible--the "stripped down" versions of all possible chemical reactions observed in a given metalloenzyme. The resulting data, generated once and for all, is then represented with mathematical formulas that are mimicking its properties realistically enough that they can be used as substitutes for the original simulations. The formulas are then used to simulate chemical reactions in their "dressed up" versions, and to study the function of any enzyme having the same general architecture as the prototype. We are interested in answering the following questions: Why is a given metalloenzyme more active bound to a certain metal than to another? In enzymes containing more than one metal atom in their active site, what is the role of each one? Which motions of the enzyme are important for its activity? Can these movements be inhibited using a small molecule? In the short term, our work will help to understand the molecular details of numerous catalytic mechanisms. In the long term, it will help to decode the function of an enzyme from its three-dimensional structure, to develop new inhibitors, and to reduce the side effects of already existing inhibitors.