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基因产物的功能，这些基因产物的序列现在是已知的。 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，但从结构中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三维结构预测蛋白质功能位点的方法。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。该方法还将独立于任何序列或结构比对或比较，使得其适用于具有很少或没有同源物的蛋白质、新折叠和工程化结构。该方法将开始于滴定曲线分析，该分析是由该小组最近开发的，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，以高精度和高精度识别催化和结合位点。此外，还将对假设进行检验，以了解该方法成功的基础。 拟议研究的最重要的智力价值要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，农业和反生物恐怖主义工作。 该项目的更广泛影响包括在生物、物理和计算科学的界面上培训学生，包括来自代表性不足群体的学生。该项目将被纳入PI的外联活动，其中包括正在进行的向包括本科生和K-12学生在内的少数民族青年促进科学事业的努力。

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.