Physically realistic homology models built with rosetta can be more accurate than their templates

doi:10.1073/pnas.0509355103

Physically realistic homology models built with rosetta can be more accurate than their templates

Department of Biochemistry, University of Washington, Box 357350, J-567 Health Sciences, Seattle, WA 98195-7350

Edited by Stephen L. Mayo, California Institute of Technology, Pasadena, CA, and approved February 3, 2006 (received for review October 26, 2005)

Abstract

We have developed a method that combines the rosetta de novo protein folding and refinement protocol with distance constraints derived from homologous structures to build homology models that are frequently more accurate than their templates. We test this method by building complete-chain models for a benchmark set of 22 proteins, each with 1 or 2 candidate templates, for a total of 39 test cases. We use structure-based and sequence-based alignments for each of the test cases. All atoms, including hydrogens, are represented explicitly. The resulting models contain approximately the same number of atomic overlaps as experimentally determined crystal structures and maintain good stereochemistry. The most accurate models can be identified by their energies, and in 22 of 39 cases a model that is more accurate than the template over aligned regions is one of the 10 lowest-energy models.

Footnotes

^§To whom correspondence should be addressed. E-mail: dabaker{at}u.washington.edu
↵ ^†Present address: Physical Biosciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS 977-152, Berkeley, CA 94720.
↵ ^‡Present address: Rosetta Inpharmatics, 401 Terry Avenue North, Seattle, WA 98109.
Author contributions: K.M.S.M., D.C., and D.B. designed research; K.M.S.M. performed research; K.M.S.M., D.C., C.A.R., D.E.K., and D.B. contributed new reagents/analytic tools; K.M.S.M. and D.B. analyzed data; and K.M.S.M. and D.B. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

PDB,

Protein Data Bank;

rmsd,

rms deviation.