Development of a Database of Protein Motions and Associated Tools

本提案的目标是构建一个蛋白质运动的工作数据库。该数据库将成为一个可公开访问的WWW社区资源，一般用于分子生物物理学社区。它将满足研究人员试图理解蛋白质结构和功能原理的需要（因为运动通常是结构和功能之间的联系）。该数据库将与基于移动界面包装的蛋白质运动分类相关联。由于一些进展，这个数据库的构建最近变得可行：已解决的蛋白质结构数量的大幅增加，连接生物数据库的基础设施的创建，以及如何使用包装来合理化蛋白质运动机制的工作。数据库的发展将分两个阶段进行，每个阶段有两个目标（一个是计算目标，另一个是生物目标）。第一阶段的主要目标将是建立一个蛋白质运动的工作原型数据库。该数据库中的运动最初将按大小（即片段，域和亚单位）分层排列，然后打包。填料分类将取决于运动是否涉及在连续维护的界面上滑动。为了实现第一个目标，有必要为蛋白质运动制定一个标准化的命名法和概念信息模型。这将包括诸如铰链数量、刚体旋转的大小以及移动接口的数量和大小等信息。在第一阶段建立的框架的基础上，该项目的第二阶段将扩展数据库和相关的运动分类。我们的目标是为每一个已知的蛋白质运动建立一个入口。此外，“推断运动”，在序列和结构同源与已知运动的蛋白质，也将包括在内。为了处理大量的数据，这将涉及分析和帮助“填充”数据库，将开发一种自动构象比较工具。这将快速对齐和比较两个任意的蛋白质构象，识别刚性核心区域，柔性铰链，界面包装差异，等等。它还将确定这些结构是否具有共享其运动的任何序列或结构同源物。数据库的扩展将需要一个更复杂的结构来描述运动之间的关系，以及一个比最初使用的大小包装层次结构更详细的运动分类方案。运动分类将通过详细的几何分析和计算进行扩展，主要集中在移动界面的包装上。

The goal of this proposal is to construct a working database of protein motions. This database will be made into a publicly accessible WWW community resource, of general use to the molecular biophysics community. It will meet the needs of researchers trying to understand the principles of protein structure and function (since motions are often the link between structure and function). The database will be associated with a classification of protein motions, based on the packing at mobile interfaces. The construction of this database has recently become feasible because of a number of developments: the great increase in the number of solved protein structures, the creation of an infrastructure of linked biological databases, and work showing how packing can be used to rationalize mechanisms for protein motions. The development of the database will proceed in two phases with two objectives in each phase (one computational and the other biological). The principal objective in the first phase will be to establish a working, prototype database of protein motions. Motions in this database will initially be arranged hierarchically in terms of size (i.e. fragment, domain, and subunit) and then packing. The packing classification will depend on whether or not the motion involves sliding over a continuously maintained interface. To achieve the first objective it will be necessary to develop a standardized nomenclature and conceptual- information model for protein motions. This will include information such as the number of hinges, the magnitude of the rigidbody rotation, and the number and size of the mobile interfaces. Building upon the framework established in the first phase, the second phase of the project will expand the database and associated motions classification. The goal will be to have an entry for every known protein motion. In addition, "inferred motions," in sequence and structure homologues of a protein with known motion, will also be included. To han dle the large amount of data this will involve analyzing and to help "populate" the database, an automatic conformation comparison tool will be developed. This will rapidly align and compare two arbitrary protein conformations, identifying rigid core regions, flexible hinges, interface packing differences, and so forth. It will also determine whether these structures have any sequence or structure homologues that share their motion. The expansion of the database will require a more sophisticated structure for describing the relationships between motions and a more detailed motion classification scheme than the size-packing hierarchy initially used. The motions classification will be expanded through detailed geometric analysis and calculation, principally focusing on the packing at mobile interfaces.