Simultaneous prediction of protein folding and docking at high resolution

doi:10.1073/pnas.0904407106

Simultaneous prediction of protein folding and docking at high resolution

^aDepartment of Biochemistry, University of Washington, Seattle WA 98195;
^bLaboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892;
^cDepartments of Chemistry and Structural Biology and Northeast Structural Genomics Consortium, State University of New York, Buffalo, NY 14260;
^dOntario Cancer Institute, Department of Medical Biophysics, and Northeast Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada M5G IL5; and
^eDepartment of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO 6310

↵²Present address: Departments of Biochemistry and Physics, Stanford University, Stanford, CA 94035.

↵¹R.D. and I.A. contributed equally to this work.
Edited by Ken A. Dill, University of California, San Francisco, CA, and approved August 7, 2009 (received for review April 21, 2009)

Abstract

Interleaved dimers and higher order symmetric oligomers are ubiquitous in biology but present a challenge to de novo structure prediction methodology: The structure adopted by a monomer can be stabilized largely by interactions with other monomers and hence not the lowest energy state of a single chain. Building on the Rosetta framework, we present a general method to simultaneously model the folding and docking of multiple-chain interleaved homo-oligomers. For more than a third of the cases in a benchmark set of interleaved homo-oligomers, the method generates near-native models of large α-helical bundles, interlocking β sandwiches, and interleaved α/β motifs with an accuracy high enough for molecular replacement based phasing. With the incorporation of NMR chemical shift information, accurate models can be obtained consistently for symmetric complexes with as many as 192 total amino acids; a blind prediction was within 1 Å rmsd of the traditionally determined NMR structure, and fit independently collected RDC data equally well. Together, these results show that the Rosetta “fold-and-dock” protocol can produce models of homo-oligomeric complexes with near-atomic-level accuracy and should be useful for crystallographic phasing and the rapid determination of the structures of multimers with limited NMR information.

Footnotes

³To whom correspondence should be addressed. E-mail: dabaker{at}u.washington.edu
Author contributions: R.D., I.A., and D.B. designed research; R.D., I.A., Y.S., Y.W., A.L., and S.B. performed research; R.D., I.A., Y.S., Y.W., A.L., S.B., C.H.A., T.S., and D.B. analyzed data; and R.D., I.A., and D.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.