Structural genomics aims to provide a good experimental structure or computational model of every tractable protein in completely sequenced genomes. We propose to computationally select targets and model molecular structures as a component of the structural genomics of Mycoplasma genitalium and Mycoplasma pneumoniae. Underlying this goal is the immense value of protein structure, especially in permitting recognition of distant evolutionary relationships for proteins whose sequence analysis has failed to find any significant homolog. A considerable fraction of the genes in all sequenced genomes have no known function or only phenotypic descriptions, and structure determination provides a direct means of revealing homology that may be used to infer putative molecular function. Structure may also help answer scientific questions arising from genomes, such as the provenance of the orphan genes unique to a particular organism. More generally, knowledge of an increasingly complete repertoire of protein structures will aid structure prediction methods, improve understanding of protein structure, and ultimately lend insight into molecular interactions and pathways. We plan to use computational methods to select families based on proteins in the Mycoplasmas for which structures cannot be predicted and which are likely to be amenable to experimental characterization. Methods to be employed included modern sequence analysis, clustering algorithms, and incorporation of other groups' analyses from public databases. The protein families will be ranked according to several criteria including taxonomic diversity and known functional information. Individual proteins will be selected from these families as targets for structure determination. The solved three-dimensional structures will be examined for similarity to other proteins of known structure. Homologous proteins in sequence databases will be computationally modeled, to provide a resource of protein structure models complementing the experimentally solved protein structures. In addition, we will develop and deploy a laboratory information management system. To keep the community apprized of our work, we will create an active web presence and also regularly submit data regularly public repositories.
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