Continued Development of Protein Dynamics Software ProDy

描述(由申请人提供)：蛋白质动力学在细胞中的分子事件中起着关键作用。计算生物学在理解和模拟构象动力学方面投入了大量的努力。为此，我们实验室引入了弹性网络模型(ENM)和谱图理论分析方法来探索结构动力学。这些方法在许多应用中都有实用价值，并帮助我们深入了解蛋白质内在的、结构编码的能力，以利于构象的特定变化，以及它们与实验观察到的功能亚态的相关性。我们已经开发了两个服务器：各向异性网络模型(ANM)和在线高斯网络模型(OGNM)，用于预测已知结构的集体动力学，在2010年已被访问超过40,000次。在实验方面，蛋白质数据库(PDB)现在拥有数百种蛋白质的多种结构，这些结构以不同的形式(例如，直系物、突变体、在变构周期中访问的亚态或不同的复合体/组装)形成相同蛋白质的异质结构数据集。我们最近的工作表明，结构的功能变化可以从这些数据集的主成分分析(PCA)中推断出来。我们还开发了一个用于分析核磁共振模型的PCA服务器(PCA_Nest)。值得注意的是，从这些实验数据集推断的信息，以及理论和计算预测的信息，可以有利地结合起来，揭示靶蛋白的激活或抑制机制，并识别调节集体运动的关键残基。出于我们研究的实用性以及我们现有软件和服务器的广泛使用，我们建议(I)改进、更新我们现有的蛋白质动力学软件，并将其整合到一个易于修改和扩展的应用程序编程接口(API)Prody中，它将允许在理论预测之外对实验数据进行系统分析，(Ii)扩展Prody API与现有序列和结构数据库的互操作性，以便能够评估特定蛋白质家族的动力学，以及(Iii)通过持续的开发和测试提高Prody的实用性，并建立其与分子动力学模拟软件的互操作。交付成果将包括两个图形用户界面(一个VMD插件和一个Chimera扩展)，以及一个数据库和网络用户界面，使没有编程经验的用户可以方便地使用该软件的全部功能。这套工具的主要用途将是阐明结构和功能之间的桥梁，不仅通过为实现这一目标而广泛利用的计算方法，而且通过提取和分析迄今积累的所有结构数据。 与公共卫生相关：现在普遍认为，蛋白质在结构上经历集体波动和合作重排的能力是实现其功能的关键。我们的实验室已经开发了各向异性网络模型(ANM)以及相关的软件和服务器，使用户能够深入了解蛋白质可访问的集体运动，同时保持其天然折叠。鉴于人们越来越认识到蛋白质动力学在定义生物分子功能机制方面的重要性，以及关于多种形式的蛋白质结构的快速增长的实验数据，我们在此建议将我们的蛋白质动力学软件Prody现代化并扩展为一个易于修改和集成的应用编程接口(API)。Prody不仅将使用广泛的实验数据和分析工具来评估蛋白质动力学，而且还将为社区提供一个数据库，其中包括经过充分研究的蛋白质家族的主要运动和可访问的构象。

DESCRIPTION (provided by applicant): Protein dynamics plays a key role in molecular events in the cell. Significant efforts in computational biology have been invested in understanding and modeling conformational dynamics. To this aim, our lab has introduced elastic network models (ENMs) and spectral graph theoretical analysis methods for exploring structural dynamics. These methods have found utility in many applications and have helped us gain insights into the intrinsic, structure-encoded ability of proteins to favor particular changes in conformation, and their relevance to experimentally observed functional substates. We have developed two servers: anisotropic network model (ANM, and the online Gaussian network model (oGNM) for predicting the collective dynamics of known structures, which have been visited over 40,000 times in 2010. On the experimental side, the Protein Data Bank (PDB) now hosts multiple structures for hundreds of proteins, which form heterogeneous structural datasets for the same protein in different forms (e.g., orthologs, mutants, substates visited during an allosteric cycle, or different complexes/assemblies). Our recent work showed that functional changes in structure may be inferred from the principal component analysis (PCA) of these datasets. We also developed a PCA server (PCA_NEST) for analyzing NMR models. Significantly, the information inferred from these experimental datasets, and those predicted by theory and computations, can be advantageously combined to disclose the mechanisms of activation or inhibition of target proteins, and to identify key residues that modulate collective movements. Motivated by the utility of our studies, and the broad use of our existing software and servers, we propose (i) to improve, modernize and integrate our existing software for protein dynamics into an easily modifiable and extensible application programming interface (API), ProDy, which will allow for systematic analysis of experimental data in addition to theoretical predictions, (ii) to extend the interoperability of ProDy API with existing sequence- and structure-databases to enable the assessment of protein family-specific dynamics and (iii) to advance the utility of ProDy through continued development and testing, and establishing its interoperation with molecular dynamics simulation software. The deliverables will include two graphical user interfaces (a VMD plugin and a Chimera extension), and a database and web user interface that will provide convenient access to the full functionality of the software by users without experience in programming. The primarily utility of this set of tools will be elucidating the bridge between structure and function, not only via computational methods that are widely exploited toward this aim, but also by extracting and analyzing all structural data accumulated to date. PUBLIC HEALTH RELEVANCE: It is now widely established that the ability of proteins to undergo collective fluctuations and cooperative rearrangements in their structure is essential to achieving their function. Our lab has developed the anisotropic network model (ANM) and related software and servers to enable users to gain insights into the collective motions accessible to proteins while maintaining their native fold. In view of the growing recognition of the significance of protein dynamics in defining the mechanisms of biomolecular function, and the rapidly growing experimental data on protein structures in multiple forms, we propose herein to modernize and extend our protein dynamics software, ProDy, into an easily modifiable and integrative application programming interface (API). ProDy will not only evaluate protein dynamics using extensive experimental data and analytical tools, but also offer the community a database of dominant motions and accessible conformers for well-studied protein families.