VIII. CONCLUSION

Whereas an experimental structure or a comparative model is generally insufficient on its own to infer the biological function of a protein, it is often complementary to sequence analysis and direct experiment. Comparative modeling efficiently increases the value of sequence information from the genome projects, although it is not yet possible to model all proteins with useful accuracy. The main bottlenecks are the absence of structurally defined members in many protein families and the difficulties in detecting weak similarities, both for fold recognition and for sequence–structure alignment. The fraction of protein sequences that can be modeled with useful accuracy by comparative modeling is increasing rapidly. The main reasons for this improvement are the increases in the numbers of known folds and the structures per fold family [16] as well as the improvement in the fold recognition and comparative modeling techniques [196]. It has been estimated that globular protein domains cluster in only a few thousand fold families, approximately 800 of which have already been structurally defined [16,23]. Assuming the current growth rate in the number of known protein structures, the structure of at least one member of most globular folds will be determined in less than 10 years [16]. According to this argument, comparative modeling would be applicable to most of the globular protein domains before the expected completion of the human genome project. However, there are some classes of proteins, including membrane proteins, that will not be amenable to modeling without improvements in structure determination and modeling techniques. For example, it has been predicted that 839 (13.9%) of the yeast ORFs have at least two transmembrane helices [235]. To maximize the number of proteins that can be modeled reliably, a concerted effort toward structural determination of the new folds by X-ray crystallography and nuclear magnetic resonance spectroscopy is in order [242]. A combination of a more complete database of known protein structures with accurate modeling techniques will efficiently increase the value of sequence information from the genome projects.

ACKNOWLEDGMENTS

We are grateful to Dr. Azat Badretdinov and Mr. Eric Feyfant for many discussions about comparative protein structure modeling. AF is a Burroughs Wellcome Fellow. RS is a Howard Hughes Medical Institute predoctoral fellow. FM is a Norman and Rosita Winston

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Biomedical Research Foundation Fellow. AS is a Sinsheimer Scholar and an Alfred P. Sloan Research Fellow. The investigations have also been aided by grants from NIH (GM 54762) and NSF (BIR-9601845).

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