THEMATICS: Development and Application of a New Computational Tool for Functional Genomics

THEMATIC（Theoretical Microscopic Titration Curves）方法作为功能基因组学和生物信息学的新工具，将得到进一步的发展和应用。 随着人类基因组和其他物种基因组的测序，大量关于蛋白质序列和结构的新信息变得可用。这一信息具有巨大的潜力，有望为人类带来许多好处。 然而，首先必须解释和理解这些基因组信息。根据这些新发现的蛋白质的结构，必须确定它们的功能。 THEMATIC方法已成功地用于定位许多不同种类蛋白质的活性位点。 该项目将开发统计分析，以改进该方法，提高其准确性，扩大其能力，并使其适合于蛋白质结构的高容量筛选自动化。 还将使用动态平均技术进一步开发该方法，以尝试扩大该方法的适用范围，分析对结构变化的敏感性，并减少假阳性结果的数量。 THEMATIC方法将发展成为一种强大的、多功能的工具，用于从蛋白质的结构中确定蛋白质的功能，并用于表征蛋白质活性位点中的残基。 此外，THEMATIC方法的结果可用于表征酶活性位点的残基，从而深入了解酶如何工作。 该项目将开发指标来描述与其他类型不同的残基，因为它们受到蛋白质环境的干扰。 这些指标将用于创建一个新的生物信息学数据库，该数据库表征残基并提供有关其在蛋白质中的功能作用的信息。 这是理解、解释和应用新测序的基因组的重要一步。 该项目将培养生物信息学和功能基因组领域研究的博士生。 THEMATIC方法还将被纳入研究生和高年级本科生分子建模和生物信息学课程的教育模块。 该项目的各个方面也将被纳入促进科学多样性的宣传活动。

The THEMATIC (Theoretical Microscopic Titration Curves) method, a new tool for functional genomics and bioinformatics, will be further developed and applied. With the sequencing of the human genome and the genomes of other species, a wealth of new information is becoming available about protein sequences and structures. This information holds tremendous potential and promise for many benefits to humankind. However, first this genomic information must be interpreted and understood. From the structures of these newly discovered proteins their function must be determined. The THEMATIC method has been used successfully to locate the active sites of a number of different kinds of proteins. The project will develop statistical analyses to improve the method, enhance its accuracy, expand its capabilities, and render it amenable to automation for high-volume screening of protein structures. This method will also be further developed using a dynamical averaging technique to attempt to expand the range of applicability of the method, analyze the sensitivity to structural changes and to reduce the number of false positive results. The THEMATIC method will be developed into a powerful, versatile tool for determining the function of a protein from its structure and for characterizing the residues in protein active sites. Furthermore, the results of the THEMATIC method can be used to characterize the residues of the active site of an enzyme and thus provide insight into how the enzyme works. The project will develop metrics to describe residues that are different from others of their type because they are perturbed by the protein environment. These metrics will be used to create a new bioinformatics database that characterizes residues and provides information about their functional role in the protein. This is an important step in the understanding, interpretation and application of the newly sequenced genome. This project will train doctoral students in research in the field of bioinformatics and functional genomes. The THEMATIC method will also be incorporated into an educational module for courses in molecular modeling and bioinformatics for graduate students and advanced undergraduates. Aspects of the project will also be incorporated into the PI's outreach activities promoting diversity in the sciences.