Automated Annotation of Function in Protein Structures from Evolutionary-based 3D-Templates

这个项目的目标是开发自动化算法来识别蛋白质结构中的功能位点，并在基因组规模上表征蛋白质功能。该方法基于进化轨迹法（Evolutionary Trace method， ET）来定位结构中的功能位点。过去的NSF支持使ET功能站点分析自动化；残基三维模板的提取；在其他结构中搜索与这些模板的几何匹配；匹配的结构执行与模板相关的功能的统计可能性。综上所述，这些步骤创建了一个完整的、自动化的功能注释管道，激发了新的目标：优化捕获功能的必要和充分决定因素的3-D模板的提取（目标1）；在我们的匹配算法中添加新的模板信息，以更好地评估分子模仿是否构成功能相似性的基础（Aim 2）；以及使用多个模板来识别功能的新策略的发展（目标3）。这一提议的广泛影响是多方面的。它将通过揭示蛋白质的哪些区域是最具生物学相关性的，从而加强生物研究基础设施，从而成为蛋白质工程和药物设计的逻辑目标。其次，通过将传统的基于蛋白质序列一维模式匹配的功能注释策略扩展到三维，开发一种新的基因产物功能表征方法。该提案还将带来健壮、标准化和易于使用的软件。高中生、本科生和研究生将参与系统的开发。该项目将通过吸引女性和少数族裔申请的校园项目扩大参与范围，目前两所大学都在提供这些项目。

PI Olivier Lichtarge, Baylor College of MedicineCo-PI Lydia Kavraki, Rice UniveristyThe goals of this project are to develop automated algorithms to identify functional sites in protein structures and to characterize protein function on a genome scale. The approach is predicated on the Evolutionary Trace method (ET) to locate functional sites in structures. Past NSF support enabled to automate functional site analysis with ET; the extraction of 3D-templates of residues; the search in other structures for geometric matches to these templates; and the statistical likelihood that matched structures perform the function associated with the template. Taken together these steps create a complete, automated functional annotation pipeline that motivates the new goals: to optimize the extraction of 3-D templates that capture the necessary and sufficient determinants of function (Aim 1); to add new template information into our matching algorithms to better evaluate whether molecular mimicry underlies functional similarity (Aim 2); and the development of novel strategies that use multiple templates to identify function (Aim 3). The broader impact of this proposal is manifold. It will strengthen biological research infrastructure by revealing which regions of proteins are most biologically relevant and hence logical targets for protein engineering and drug design. Second, it will develop a novel method for functional characterization of gene products by extending to three dimensions a functional annotation strategy traditionally based on one-dimensional pattern matching in protein sequences. The proposal will also lead to software that is robust, standardized, and easy to use. High-school, undergraduates and graduate students will participate in the development of the system. The project will broaden participation using campus programs that attract female and minority applications and are being offered at both institutions.