Development of the flexible comparative modeling toolkit

描述（由申请人提供）：结构生物学为我们提供了数万个蛋白质三维结构的例子，这些例子给出了许多重要生物过程的分子水平信息。所有这些结构的坐标都存储在蛋白质数据库中，可供下载和进一步分析。大多数PDB用户感兴趣的是与特定生物学问题相关的特定蛋白质，但相同的是， 数据也可以不针对单个蛋白质的特定特征进行分析，而是识别描述蛋白质结构的规则，这些规则又可以用于蛋白质结构预测， 仿真。后一种方法被成功地用于推导经验势和规则，这些规则被用于罗塞塔等程序。然而，项目数据库现有数据中所载的大量信息仍未得到利用，主要是因为缺乏适当的软件工具。 在这里，我们建议挖掘PDB中包含的信息的结构密切相关，甚至相同的蛋白质。我们认为，这种情况下，删除“冗余”在大多数现存的蛋白质结构分析，提供了独特的，即使是间接的，信息蛋白质的灵活性，特别是方式和方向，其中各种蛋白质折叠改变的结构。 结构响应突变（进化灵活性），或激活或配体结合（功能灵活性）。作为我们分析的结果，我们预期得出关于 蛋白质结构变化，可以应用于加速和/或直接模拟的规则，并且可以用于预测直接实验不可用的功能状态下的蛋白质构象。 该提案的主要成果是一个“灵活的比较建模”工具包，一系列算法和协议，允许用户将蛋白质结构变化的经验规则应用于他们感兴趣的蛋白质。该工具包可从 项目网站作为一个服务器，但也将作为一个开源软件包分发。 公共卫生相关性：在这个项目中，我们建议开发一个灵活的比较建模工具包，程序和服务器，这将提供一种简单快速的方法来预测其他功能状态下的蛋白质结构，从而为基于能量的外推和改进提供一种快速廉价的替代方案，并有助于更快的药物开发和更容易的重要蛋白质靶点的功能分析。

DESCRIPTION (provided by applicant): Structural biology provided us with tens of thousands of examples of protein three- dimensional structures, which gave molecular level information about many important biological processes. Coordinates of all these structures are deposited to a Protein Data Bank, where they are available for downloads and further analysis. Most of PDB users are interested in specific proteins relevant to a particular biological problem, but the same data can also be analyzed not for specific features of individual proteins, but to identify empiricl rules describing protein structures, which in turn can be used in protein structure predictions and simulations. The latter approach was used successfully to derive empirical potentials and rules that are used in programs such as Rosetta. However, a significant amount of information contained in the data available in the PDB is still untapped, mostly because of lack of adequate software tools. Here we propose to mine the PDB for information contained in structures of closely related or even identical proteins. We argue, that such cases, removed as "redundant" in most extant analyses of protein structures, provide unique, even that indirect, information about protein flexibility and specifically, ways and directions in which various protein folds change the structure in response to mutations (evolutionary flexibility), or to activation or ligand binding (functional flexibility). As a result of our analysis, we anticipate deriving empirical rules about protein structural changes, rules that can be applied to speed up and/or direct simulations and can be used to predict conformations of proteins in functional states unavailable from the direct experiment. The main deliverable of this proposal would be a "flexible comparative modeling" toolkit, a series of algorithms and protocols which would allow the users to apply empirical rules of protein structure changes to their protein of interest. This toolkit would be available from the project website as a server, but also would be distributed as an open source software package. PUBLIC HEALTH RELEVANCE: In this project we propose to develop a flexible comparative modeling toolkit, program and server that would provide a simple and fast way to predict structures of proteins in other functional states, thus, providing a fast and cheap alternative to energy based extrapolations and refinements and contributing to faster drug development and easier functional analysis of important protein targets.