Protein Structure-Based Prediction of Functional Information

基因组研究中最重要的任务之一是发现许多序列已知的基因产物的功能。结构基因组学的努力正在迅速增加这些基因产物的已知三维结构的数量，但从结构确定功能已被证明是困难的。该项目的目标是开发和实施一种仅从蛋白质的三维结构预测功能位点的方法。这种方法将是快速的，因此它可以在高通量的基础上分析结构。该方法也将独立于任何序列或结构比对或比较，因此它适用于具有很少或没有同源物的蛋白质，新折叠和工程结构。该方法将从该小组最近开发的滴定曲线分析开始，并专门用于功能位点鉴定。现在，这些分析将与其他基于结构的计算相结合，以高度的准确性和精度识别催化和结合位点。此外，还将对假设进行测试，以了解该方法成功的基础。提出的研究最重要的智力价值元素是开发了一种独特的方法来帮助分析和解释结构基因组学数据。预测基因产物功能的能力在分子生物学以外的领域具有广泛的影响，包括植物科学、农业和反恐努力。该项目的更广泛影响包括培养学生，包括来自代表性不足群体的学生，在生物、物理和计算科学的界面上。该项目将纳入PI的外展活动，其中包括正在努力促进少数民族青年，包括本科生和K-12学生在科学领域的职业。

One of the most important tasks in genome research is to discover the function of the many gene products whose sequences are now known. Structural genomics efforts are rapidly increasing the number of known three-dimensional structures of these gene products, but the determination of function from the structure has proved to be difficult. The goals of this project are to develop and implement a methodology for the prediction of functional sites in proteins from their three-dimensional structures alone. This method will be fast, so that it can analyze structures on a high-throughput basis. The method will also be independent of any sequence or structure alignments or comparisons, so that it is applicable to proteins with few or no homologues, to novel folds, and to engineered structures. The method will begin with the titration curve analyses that have recently been developed by this group and tested specifically for functional site identification. Now these analyses will be coupled with other structure-based calculations, to identify catalytic and binding sites with high degree of accuracy and precision. In addition, hypotheses will be tested in order to understand the basis for the success of the method. The most significant element of intellectual merit of the proposed study is the development of a unique method to aid in the analysis and interpretation of structural genomics data. The ability to predict the function of gene products has broad impact in areas beyond molecular biology, including plant science, agriculture, and counter-bioterrorism efforts. The broader impact of this project includes the training of students, including students from underrepresented groups, at the interface of the biological, physical, and computational sciences. The project will be incorporated into the PI's outreach activities, which include ongoing efforts to promote careers in the sciences to minority youth, including undergraduates and K-12 students.