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.