title: Algorithm for backrub motions in protein design.
abstract: BACKGROUND
  The Backrub is a small but kinematically efficient side-chain-coupled local backbone motion frequently observed in atomic-resolution crystal structures of proteins. A backrub shifts the C(alpha)-C(beta) orientation of a given side-chain by rigid-body dipeptide rotation plus smaller individual rotations of the two peptides, with virtually no change in the rest of the protein. Backrubs can therefore provide a biophysically realistic model of local backbone flexibility for structure-based protein design. Previously, however, backrub motions were applied via manual interactive model-building, so their incorporation into a protein design algorithm (a simultaneous search over mutation and backbone/side-chain conformation space) was infeasible.
  
  
  RESULTS
  We present a combinatorial search algorithm for protein design that incorporates an automated procedure for local backbone flexibility via backrub motions. We further derive a dead-end elimination (DEE)-based criterion for pruning candidate rotamers that, in contrast to previous DEE algorithms, is provably accurate with backrub motions. Our backrub-based algorithm successfully predicts alternate side-chain conformations from < or = 0.9 A resolution structures, confirming the suitability of the automated backrub procedure. Finally, the application of our algorithm to redesign two different proteins is shown to identify a large number of lower-energy conformations and mutation sequences that would have been ignored by a rigid-backbone model.
  
  
  BACKGROUND
  Contact authors for source code.
authors.affiliation: Department of Computer Science, Duke University, Durham, NC 27708, USA.
authors.forename: Ivelin
authors.initials: I
authors.lastname: Georgiev
authors.forename: Daniel
authors.initials: D
authors.lastname: Keedy
authors.forename: Jane S
authors.initials: JS
authors.lastname: Richardson
authors.forename: David C
authors.initials: DC
authors.lastname: Richardson
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Donald
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D008969:Molecular Sequence Data; D009154:Mutation; D015202:Protein Engineering / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D020539:Sequence Analysis, Protein / Q000379:methods*; D013329:Structure-Activity Relationship
chemical_list: D011506:Proteins