Algorithmic assignment of probable function to proteins of previously unknown fun

描述（由申请人提供）：对先前未知功能的蛋白质进行可能函数的算法分配目标和具体目的：本项目的目标是扩展和应用在为当前未知功能的PDB条目分配可能函数方面表现出希望的算法。这应该有助于从蛋白质结构计划中获益，“帮助研究人员阐明结构-功能关系，从而制定更好的假设和设计更好的实验。”研究设计和方法：新的蛋白质结构正在以比其生物学功能更快的速度被确定。目前蛋白质数据库中分类为“未知功能”的条目有2939条。许多计算方法已经被开发出来，为这些结构提供快速、廉价的功能预测手段，包括那些专注于整个主干的排列，以及其他专注于基于蛋白质结构中异常电荷分布的活性位点残基的识别和排列的方法。我们为PyMOL分子图形环境开发了一个名为ProMOL的软件插件，它依赖于酶催化位点中保守的几何关系。ProMOL中的基序是根据催化位点图谱（CSA） （http://www.ebi.ac.uk/thornton-srv/databases/CSA/）中的活性位点规格创建的。我们的方法根据特定的原子几何形状明确地搜索CSA定义的催化位点残基，在概念上类似于CSA JESS模板。这就省去了过滤掉诸如保守折叠结构域或配体结合区等混杂元素的需要。对丝氨酸蛋白酶和过氧化物酶家族的结构文件进行了广泛的测试，证实了催化残基的几何关系对蛋白质结构的功能预测是有效和充分的。除了对丝氨酸蛋白酶和过氧化物酶进行广泛的表征外，我们还使用Motif Finder对39个被归类为“结构基因组学，未知功能”的PDB条目进行了初步研究，其中包含22个“原生”ProMOL基序，以及相应的CSA JESS C1C2基序和CSA功能原子基序。在研究的39个条目中，26个（67%）的预测值为1（与现有模板完全匹配）。在36个（92%）结构中发现了缺乏一个残基或含有额外（异常）残基的活性位点。只有三个测试用例中没有报告匹配。我们将在ProMOL的Motif Finder中扩展Motif的数量，使用新创建的ProMOL Motif和现有的JESS Motif来包括最突出的蛋白质家族的代表，增加过程的自动化，然后评估所有被描述为具有“未知功能”的PDB条目。显示正相关的条目将使用序列和结构比对工具进一步探索。软件和结果都将向社区公开发布。

DESCRIPTION (provided by applicant): Algorithmic assignment of probable function to proteins of previously unknown function Objectives and Specific Aims: The goal of this project is to extend and apply algorithms that show promise in assigning a probable function for PDB entries of currently unknown function. This should contribute to deriving benefit from the Protein Structure Initiative by "help[ing] researchers illuminate structure-function relationships and thus formulate better hypotheses and design better experiments." Research Design and Methods: New protein structures are being determined at a rate faster than their biological function can be assigned. There are currently 2939 entries in the Protein Data Bank with the classification "Unknown Function". A number of computational methods have been developed to provide rapid, inexpensive means of function prediction for these structures, including those that focus on alignment of entire backbones and others that focus on identification and alignment of active site residues based on the unusual charge distributions in protein structures. We have developed a software plug-in for the PyMOL molecular graphics environment called ProMOL that relies on the geometric relationships conserved in enzyme catalytic sites. Motifs in ProMOL were created from the active site specifications found in the Catalytic Site Atlas (CSA) (http://www.ebi.ac.uk/thornton-srv/databases/CSA/). Our approach explicitly searches for CSA- defined catalytic site residues according to specific atomic geometry, similar in concept to the CSA JESS templates. This dispenses with the need to filter out confounding elements such as conserved folding domains or ligand binding regions. Extensive testing of structural files from the serine protease and peroxidase families confirmed that the geometric relationships of catalytic residues alone are effective and sufficient for function prediction in protein structures. In addition to extensive characterization of serine proteases and peroxidases, we also performed a preliminary study of 39 PDB entries classified as "Structural Genomics, Unknown Function" using the Motif Finder in ProMOL, which contains 22 "native" ProMOL motifs, along with the corresponding CSA JESS C1C2 motifs and CSA Functional Atom motifs. Of the 39 entries studied, 26 (67%) yielded prediction values of 1 (exact match to an existing template). An active site lacking one residue or containing an extra (outlier) residue was identified for 36 (92%) of the structures. No match was reported in only three of the test cases. We will extend the number of motifs in ProMOL's Motif Finder, using both newly created ProMOL motifs and existing JESS motifs to include representatives from the most prominent protein families, increase automation of the process and then evaluate all PDB entries described as having "unknown function". Entries that show positive correlation will then be further explored using sequence and structure alignment tools. Both software and results will be openly released to the community.