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Published online on February 14, 2006, 10.1073/pnas.0509379103
PNAS | February 21, 2006 | vol. 103 | no. 8 | 2605-2610


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BIOLOGICAL SCIENCES / BIOPHYSICS
On the origin and highly likely completeness of single-domain protein structures

Yang Zhang*, Isaac A. Hubner{dagger}, Adrian K. Arakaki*, Eugene Shakhnovich{dagger}, and Jeffrey Skolnick*,{ddagger}

*Center of Excellence in Bioinformatics, University at Buffalo, State University of New York, 901 Washington Street, Buffalo, NY 14203; and {dagger}Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138

Edited by Harold A. Scheraga, Cornell University, Ithaca, NY, and approved December 30, 2005 (received for review October 27, 2005)

The size and origin of the protein fold universe is of fundamental and practical importance. Analyzing randomly generated, compact sticky homopolypeptide conformations constructed in generic simplified and all-atom protein models, all have similar folds in the library of solved structures, the Protein Data Bank, and conversely, all compact, single-domain protein structures in the Protein Data Bank have structural analogues in the compact model set. Thus, both sets are highly likely complete, with the protein fold universe arising from compact conformations of hydrogen-bonded, secondary structures. Because side chains are represented by their Cbeta atoms, these results also suggest that the observed protein folds are insensitive to the details of side-chain packing. Sequence specificity enters both in fine-tuning the structure and thermodynamically stabilizing a given fold with respect to the set of alternatives. Scanning the models against a three-dimensional active-site library, close geometric matches are frequently found. Thus, the presence of active-site-like geometries also seems to be a consequence of the packing of compact, secondary structural elements. These results have significant implications for the evolution of protein structure and function.

evolution | Protein Data Bank | protein folding | protein structure prediction

Author contributions: Y.Z., I.A.H., A.K.A., E.S., and J.S. designed research, performed research, contributed new reagents/analytic tools, analyzed data, and wrote the paper.

Conflict of interest statement: No conflicts declared.

This paper was submitted directly (Track II) to the PNAS office.

{ddagger}To whom correspondence should be sent at the present address: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 250 14th Street NW, Atlanta, GA 30318. E-mail: skolnick{at}gatech.edu

© 2006 by The National Academy of Sciences of the USA


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