Functional Differentiation of Proteins: Implications for Structural Genomics Running Title: Functional Differentiation of Proteins

Structural genomics is a broad initiative of various centers aiming to provide a complete coverage of protein structure space. Since it is not feasible to experimentally determine the structures of all proteins, it is generally agreed that the only viable strategy to achieve such coverage is to carefully 2 select specific proteins (" targets "), determine their structure experimentally, and then use comparative modeling techniques to model the rest. Here we suggsest that structural genomics centers refine the structure-driven approach in target selection by adopting function-based criteria. We suggest targeting functionally divergent superfamilies within a given structural fold so that each function receives a structural characterization. We have developed a method to do so, and an itemized survey of several functionally rich folds shows that they are only partially functionally characterized. We call upon structural genomics centers to consider this approach and upon computational biologists to further develop function-based targeting methods.