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Published online on March 7, 2008, 10.1073/pnas.0800256105
PNAS | March 25, 2008 | vol. 105 | no. 12 | 4685-4690


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From the Cover
BIOLOGICAL SCIENCES / BIOPHYSICS
Consistent blind protein structure generation from NMR chemical shift data

Yang Shen*, Oliver Lange{dagger}, Frank Delaglio*, Paolo Rossi{ddagger}, James M. Aramini{ddagger}, Gaohua Liu{ddagger}, Alexander Eletsky§, Yibing Wu§, Kiran K. Singarapu§, Alexander Lemak, Alexandr Ignatchenko, Cheryl H. Arrowsmith, Thomas Szyperski§, Gaetano T. Montelione{ddagger}, David Baker{dagger},||, and Ad Bax*,||

*Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; {dagger}Department of Biochemistry and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195; {ddagger}Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, and Northeast Structural Genomics Consortium, Rutgers, The State University of New Jersey, and Robert Wood Johnson Medical School, Piscataway, NJ 08854; §Departments of Chemistry and Structural Biology and Northeast Structural Genomics Consortium, University at Buffalo, State University of New York, Buffalo, NY 14260; and Ontario Cancer Institute, Department of Medical Biophysics, and Northeast Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G IL5

Contributed by Ad Bax, January 10, 2008 (received for review December 14, 2007)

Protein NMR chemical shifts are highly sensitive to local structure. A robust protocol is described that exploits this relation for de novo protein structure generation, using as input experimental parameters the 13C{alpha}, 13Cβ, 13C', 15N, 1H{alpha} and 1HN NMR chemical shifts. These shifts are generally available at the early stage of the traditional NMR structure determination process, before the collection and analysis of structural restraints. The chemical shift based structure determination protocol uses an empirically optimized procedure to select protein fragments from the Protein Data Bank, in conjunction with the standard ROSETTA Monte Carlo assembly and relaxation methods. Evaluation of 16 proteins, varying in size from 56 to 129 residues, yielded full-atom models that have 0.7–1.8 Å root mean square deviations for the backbone atoms relative to the experimentally determined x-ray or NMR structures. The strategy also has been successfully applied in a blind manner to nine protein targets with molecular masses up to 15.4 kDa, whose conventional NMR structure determination was conducted in parallel by the Northeast Structural Genomics Consortium. This protocol potentially provides a new direction for high-throughput NMR structure determination.

molecular fragment replacement | protein structure prediction | ROSETTA | structural genomics

Author contributions: Y.S., D.B., and A.B. designed research; Y.S. and O.L. performed research; F.D. contributed new reagents/analytic tools; Y.S., P.R., J.M.A., G.L., A.E., Y.W., K.K.S., A.L., and A.I. analyzed data; and Y.S., C.H.A., T.S., G.T.M., D.B., and A.B. wrote the paper.

The authors declare no conflict of interest.

See Commentary on page 4533.

This article contains supporting information online at www.pnas.org/cgi/content/full/0800256105/DC1.

||To whom correspondence may be addressed. Email: dabaker{at}u.washington.edu or bax{at}nih.gov

© 2008 by The National Academy of Sciences of the USA


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Related Commentary in PNAS:

Local knowledge helps determine protein structures
Michael R. Gryk and Jeffrey C. Hoch
PNAS 2008 105: 4533-4534. [Extract] [Full Text]  



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M. R. Gryk and J. C. Hoch
Local knowledge helps determine protein structures
PNAS, March 25, 2008; 105(12): 4533 - 4534.
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