Algorithm for backrub motions in protein design.

Published

Journal Article

MOTIVATION: 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. AVAILABILITY: Contact authors for source code.

Full Text

Duke Authors

Cited Authors

  • Georgiev, I; Keedy, D; Richardson, JS; Richardson, DC; Donald, BR

Published Date

  • July 1, 2008

Published In

Volume / Issue

  • 24 / 13

Start / End Page

  • i196 - i204

PubMed ID

  • 18586714

Pubmed Central ID

  • 18586714

Electronic International Standard Serial Number (EISSN)

  • 1367-4811

Digital Object Identifier (DOI)

  • 10.1093/bioinformatics/btn169

Language

  • eng

Conference Location

  • England