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

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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.