Alignment Tools for the Conserved Domain Database

该项目包含两个相关的软件开发工作。两者都旨在支持保存的域数据库CDD的管理员和用户，如项目LM000161-03中单独描述的那样。第一项工作涉及算法的开发和计算测试，以产生不同蛋白质序列的准确比对。第二个涉及开发交互工具，用于比对和识别蛋白质家族中的亚家族结构。 基于结构的比对算法的开发建立在我们小组早期关于蛋白质线的工作的基础上。这些方法通过结构模板“穿线”蛋白质序列，通过能量计算、使用接触电势和从模板的蛋白质家族获得的序列图谱来对备选比对进行评分。这些方法的成功在1998年的CASP3研讨会上得到了展示，在参加比赛的90多个国际小组中，NCBI团队被折叠识别授予结构预测方面的“第一名”。为了使这些方法适应CDD策展人所需的高吞吐量对齐，我们开发了用于线程的块对齐算法的更高效版本。今年的工作表明，这种方法产生的比对足够准确，可以识别保守的功能位点，并且相对于原始的穿线方法，信息损失最小。在目前的工作中，我们正在评估一种自动多重比对算法的性能，该算法在明显的亚家族树CDD组中迭代地应用基于结构的比对。 基于结构的比对交互工具的开发涉及到将这些算法集成到Cn3D比对编辑器中。添加了几个新功能，包括最新版本的块对齐。该软件是CDD馆长团队的日常使用软件，具有这些功能的新版本已经广泛分发。进一步工作的重点是开发CDTree比对层次编辑系统，CDD馆长小组也在日常使用该系统。该软件在交互式软件包中实现了一套用于蛋白质家族分子进化分析的工具。它支持使用文献中的几种算法生成系统发育序列树，这些算法链接到生物分类树的显示和整个蛋白质结构域结构的总结。该软件还支持自动搜索每日更新的序列和结构数据库以寻找每个家族的新成员，选择新的相似性和/或分类学组的非冗余代表的“更新”程序。CDTree子家族层次结构编辑器可与Cn3D比对编辑器无缝通信，使馆长用户能够轻松检测和纠正由比对或序列错误引起的“异常值”。虽然CDTree是为CDD策展人的需要而设计的，但它也可以用作简单的查看器，以直观的图形显示CDD家族层次结构中的序列、分类和功能多样性。作为观众的公开发行计划在来年进行。

This project encompasses two related software development efforts. Both are intended to support both curators and users of the Conserved Domain Database, CDD, as described separately in project LM000161-03. The first effort involves is development and computational testing of algorithms to produce accurate alignments for diverse protein sequences. The second involves development of interactive tools for aligning and identifying subfamily structure within a protein family. Development of structure-based alignment algorithms builds upon our group's earlier work on protein threading. These methods "thread" a protein sequence through a structural template, scoring alternative alignments by energy calculations, using contact potentials, and a sequence profile derived from the protein family of the template. The success of these methods were demonstrated at the 1998 CASP3 workshop, where the NCBI team was awarded "first place" in structure prediction by fold recognition, among over 90 international groups entering the competition. To adapt these methods to the high throughput alignment as needed by CDD curators we have developed more efficient versions of the block-alignment algorithm used in threading. Work this year has shown that this method produces alignments accurate enough for identification of conserved functional sites, and that information loss relative to the original threading method is minimal. In current work we are evaluating the performance of an automated multiple alignment algorithm that applies structure-based alignment iteratively, across the apparent subfamily tree CDD groups. Development of interactive tools for structure-based alignment has involved integration of these algorithms into the Cn3D alignment editor. Several new functions have been added, including the latest version of block alignment. This software is in daily use by the CDD curator team and a new version with these functions has been widely distributed. Further work has focused on development of the CDTree alignment hierarchy editing system, which is also in daily use by the CDD curator team. This software implements a suite of tools for molecular evolutionary analysis of protein families in an interactive package. It supports generation of phylogenetic sequence trees using several algorithms from the literature, linked to displays of organism taxonomy trees and summaries of overall protein domain architecture. The software also supports an "update" procedure that automatically searches the daily-updated sequence and structure databases for new members of each family, selecting non-redundant representatives of new similarity and/or taxonomy groups. The CDTree subfamily hierarchy editor communicates seamlessly with the Cn3D alignment editor, allowing curator-users to easily detect and correct "outliers" caused by alignment or sequence errors. While designed for the needs of CDD curators, CDTree may also be used as a simple viewer, showing in intuitive graphical displays the sequence, taxonomic and functional diversity within a CDD family hierarchy. Public release as a viewer is planned for the coming year.