With this award, the Chemistry of Life Processes Program in the Chemistry Division and the Molecular Biophysics program in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences support Dr. George Rose from Johns Hopkins University to enumerate a complete set of protein domains from chemical principles. The identification of protein domains dates back at least four decades, and dozens of structure-based domain definitions have been proposed. Perhaps the most enduring definition, potentially independent, stable folding units, conveys the fundamental concept qualitatively. Yet, whether or not a protein substructure folds independently cannot be ascertained from its structure, and stability depends on folding conditions such as temperature, pressure, and solvent quality. Recently the Rose group introduced a novel thermodynamic framework to assess domains. This approach transforms decades of fuzzy structural domain definitions into a thermodynamically rigorous definition. With this transformation in place, the set of possible domains can now be generated based on the chemical principles that govern accessible conformations of polypeptide chains in aqueous solvent. This set can then be classified and compiled into a reference library. To test the library for accuracy and completeness, protein structures in the protein data bank (PDB) will be mapped onto their corresponding reference library counterparts, and conversely, reference library entries will be mapped into instances of these structures in the PDB. It is anticipated that multiple validation cycles and much fine-tuning will be needed to achieve self-consistency and completeness.
Domains are the fundamental building blocks of proteins. It is hypothesized that only a few thousand distinct architectures can be realized by a domain-sized protein, a limitation imposed by the chemistry of the protein backbone in water. If validated, the domains hypothesis would exert a broad influence on future directions in protein science and biochemistry in general. The ultimate goal is to develop a complete modular parts list of structural domains and use it to reconstruct the evolutionary past of protein molecules. En route to that goal, this inquiry is expected to provide a practical framework for protein engineering and for assessing current whole genome-based initiatives. The principal investigator will provide close personal mentorship for a postdoctoral researcher dedicated to this project and at its conclusion will write a book describing the outcomes of this research for the general public.
