Algorithm for backrub motions in protein design Export

@article{citeulike:3687035, abstract = {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 [\≤]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. Contact: brd+ismb08@cs.duke.edu 10.1093/bioinformatics/btn169}, author = {Georgiev, Ivelin and Keedy, Daniel and Richardson, Jane S. and Richardson, David C. and Donald, Bruce R.}, citeulike-article-id = {3687035}, citeulike-linkout-0 = {http://dx.doi.org/10.1093/bioinformatics/btn169}, citeulike-linkout-1 = {http://bioinformatics.oxfordjournals.org/cgi/content/abstract/24/13/i196}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/18586714}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=18586714}, day = {1}, doi = {10.1093/bioinformatics/btn169}, issn = {1460-2059}, journal = {Bioinformatics}, keywords = {backrub, structural\_bioinformatics}, month = {July}, number = {13}, pages = {i196--204}, posted-at = {2008-11-25 13:29:05}, priority = {2}, title = {Algorithm for backrub motions in protein design}, url = {http://dx.doi.org/10.1093/bioinformatics/btn169}, volume = {24}, year = {2008} }

TY - JOUR ID - citeulike:3687035 L3 - citeulike-article-id:3687035 N2 - 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 [≤]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. Contact: brd+ismb08@cs.duke.edu 10.1093/bioinformatics/btn169 IS - 13 JF - Bioinformatics SN - 1460-2059 EP - 204 TI - Algorithm for backrub motions in protein design VL - 24 SP - i196 KW - backrub KW - structural_bioinformatics AU - Georgiev, Ivelin AU - Keedy, Daniel AU - Richardson, Jane AU - Richardson, David AU - Donald, Bruce PY - 2008/07/01/ UR - http://dx.doi.org/10.1093/bioinformatics/btn169 ER -