Alignment Tools for the Conserved Domain Database

保守域数据库的比对工具

• 批准号: 6988452
• 负责人: STEPHEN H. BRYANT
• 金额: --
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6988452
• 关键词: biochemical evolution; chemical models; computer assisted sequence analysis; computer simulation; computer system design /evaluation; information display; information retrieval; method development; model design /development; molecular biology information system; protein folding; protein sequence; protein structure; statistics /biometry; structural biology

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.

该项目包括两个相关的软件开发工作。两者都旨在支持保守域数据库CDD的管理者和用户，如项目LM 000161 -03中单独描述的。第一个努力涉及的是算法的开发和计算测试，以产生不同蛋白质序列的精确比对。第二个涉及开发交互式工具，用于在蛋白质家族内对齐和识别亚家族结构。 基于结构的比对算法的开发建立在我们小组早期对蛋白质线程的工作基础上。这些方法将蛋白质序列“穿线”通过结构模板，通过能量计算、使用接触电势和源自模板的蛋白质家族的序列谱来对备选比对进行评分。这些方法的成功在1998年的CASP 3研讨会上得到了展示，NCBI团队在90多个参加比赛的国际团体中获得了折叠识别结构预测的“第一名”。为了使这些方法适应CDD管理员所需的高吞吐量对齐，我们开发了线程中使用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精确，可以识别保守的功能位点，并且相对于原始的线程方法，信息损失最小。在目前的工作中，我们正在评估一个自动化的多对齐算法，适用于基于结构的对齐迭代的性能，在整个明显的子家族树CDD组。 基于结构的比对的交互式工具的开发涉及将这些算法集成到Cn 3D比对编辑器中。添加了几个新功能，包括最新版本的块对齐。CDD管理员团队日常使用该软件，具有这些功能的新版本已广泛分发。进一步的工作集中在CDTree对齐层次编辑系统的开发上，该系统也是CDD策展人团队日常使用的。该软件实现了一套工具的蛋白质家族的分子进化分析在一个互动的包。它支持使用文献中的几种算法生成系统发育序列树，与生物分类树的显示和整体蛋白质结构域架构的总结相关联。该软件还支持“更新”程序，该程序自动搜索每日更新的序列和结构数据库中每个家族的新成员，选择新相似性和/或分类组的非冗余代表。CDTree子家族层次编辑器与Cn 3D比对编辑器无缝通信，允许管理员用户轻松检测和纠正由比对或序列错误引起的“离群值”。虽然CDTree是为CDD管理者的需求而设计的，但它也可以用作一个简单的查看器，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。计划明年作为观众公开发行。