The dynamic ensemble: exploring accessible conformational space

我们体内细胞的功能取决于分子复合物（通常是复杂的）在时间和位置上的正确组装，这些分子复合物几乎总是包含蛋白质。为了理解这些所谓的分子机器的功能，我们必须知道它们的“外观”，即我们需要知道组成蛋白质分子的所有原子在三维（3D）空间中的排列。此外，这些排列不是静态的;随着时间的推移，蛋白质分子会振动，变形和适应其形状以响应其环境。很明显，这些动态适应是这些蛋白质的功能作用的关键，因此，这产生了深刻的兴趣，研究这种动态特性的方法。结构生物学是生物科学的一个领域，研究3D生物分子结构，它们的动力学和它们的相互作用。这些结构的知识在科学的许多领域是必不可少的，并帮助我们了解生命和疾病过程的分子基础，设计更好的药物，提高在食品，造纸或农业等行业中使用的酶的效率。X射线晶体学和核磁共振（NMR）光谱是产生绝大多数生物分子结构的两种技术。蛋白质数据库（PDB）是一个全球性的生物分子结构数据库，在超过10万个条目中，大约86%是使用X射线晶体学确定的，而13%来自NMR。X射线结构通常在低温（-173 ℃）下以结晶状态测定，该技术不能自然地揭示有关动态特性的信息。相反，NMR数据是在室温下在溶液中获得的，并且固有地受到在大范围时间尺度上发生的动态平均过程的影响。这既是一个麻烦，也是一个机会。该提案旨在开发技术，从容易获得的NMR数据中提取有关蛋白质动力学的知识。我们假设这些信息本质上足以推导出动态代表性的结构系综，从而更好地解释实验数据和实际蛋白质构象。具体而言，我们计划：1。设计和测试一个软件管道，用于从现成的NMR数据中提取有关蛋白质的动态信息，并将其转换为易于可视化的形式。使用PDB中包含的NMR衍生蛋白质结构的管道进行大规模重新计算。3.利用动态代表性结构系综测试和探索小分子对接的效果.为NMR社区建立一个可普遍访问的服务器，以便在他们自己的项目中执行管道。来自世界各地的学术和工业研究人员将结构信息存储在PDB中。我们认为，更好地表示动态信息将增加这些数据的价值，产生更高的质量和更相关的结果，供其他科学家使用，以促进我们的知识和人类健康，药物发现，农业等的理解。该项目将在莱斯特教授的监督下进行，Vuister教授是该领域的知名专家。莱斯特的综合结构生物学研究环境提供了一个伟大的科学基础设施和支持。此外，许多其他专家也参与并支持该项目，从而扩大了其影响。

The functioning of the cells in our bodies is dependent upon the proper assembly, in time and location, of (often complicated) molecular complexes, that nearly always contain proteins. To understand the functioning of these so-called molecular machines, it is imperative that we know how they 'look', i.e. we need to know the arrangement of all the atoms that comprise the protein molecule in three-dimensional (3D) space. Moreover, these arrangements are not static; the protein molecules vibrate, deform and adapt their shape in response to their environment over time. It has become clear that these dynamic adaptations are key to the functional roles of these proteins and hence this has generated a profound interest in ways to study such dynamical properties.Structural biology is a field of biological science that studies 3D biomolecular structures, their dynamics and their interactions. Knowledge of these structures is essential in many areas of science and helps us understand the molecular basis of life and disease processes, design better drugs, improve the efficiency of enzymes used in the food, paper or agriculture industry, etc.X-ray crystallography and Nuclear Magnetic Resonance (NMR) spectroscopy are the two techniques that produce the overwhelming majority of biomolecular structures. Of the more than 100000 entries in the Protein Data Bank (PDB), a global repository for biomolecular structures, about 86% were determined using X-ray crystallography, while 13% come from NMR. X-ray structures are typically determined at a low temperature (-173 degree C) in a crystalline state and the technique does not naturally reveal information regarding dynamic properties. In contrast, the NMR data are acquired at room temperature in solution and are inherently affected by dynamic averaging processes occurring on a large range of time scales. This presents both a nuisance and an opportunity.This proposal aims to develop technology to extract knowledge about protein dynamics from easily available NMR data. We postulate that this information is inherently sufficient to derive a dynamically-representative structural ensemble that better accounts for both the experimental data and the actual protein conformation. Specifically, we plan to:1. Design and test a software pipeline for extraction of this dynamical information about proteins from readily available NMR data and convert it into an easily visualized form.2. Conduct a large-scale re-computation using the pipeline of the NMR-derived protein structures contained in the PDB.3. Test and explore the effect of small molecule docking using dynamically-representative structural ensembles.4. Setup a generally accessible server for the NMR community to execute the pipeline on their own projects.The structural information is deposited in the PDB by academic and industrial researchers from all over the world. We think that the better representation of dynamical information will increase the value of this data, yielding higher quality and more relevant result for usage by other scientists to advance our knowledge and understanding of human health, drug discovery, agriculture, etc.The project will be conducted in Leicester under the supervision of Prof. Vuister, a well-known expert in the field. Leicester's integrated structural biology research environment provides for a great scientific infrastructure and support. In addition, numerous other experts are connected to and support the project as well, thus extending its impact.