De Novo Computational Design of Retro-Aldol Enzymes

@article{citeulike:2481463, abstract = {The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model. 10.1126/science.1152692}, author = {Jiang, Lin and Althoff, Eric A. and Clemente, Fernando R. and Doyle, Lindsey and Rothlisberger, Daniela and Zanghellini, Alexandre and Gallaher, Jasmine L. and Betker, Jamie L. and Tanaka, Fujie and Barbas, Carlos F. and Hilvert, Donald and Houk, Kendall N. and Stoddard, Barry L. and Baker, David }, citeulike-article-id = {2481463}, doi = {10.1126/science.1152692}, journal = {Science}, keywords = {design, prediction, protein}, month = {March}, number = {5868}, pages = {1387--1391}, posted-at = {2008-03-07 03:02:39}, priority = {2}, title = {De Novo Computational Design of Retro-Aldol Enzymes}, url = {http://dx.doi.org/10.1126/science.1152692}, volume = {319}, year = {2008} }

TY - JOUR ID - citeulike:2481463 L3 - citeulike-article-id:2481463 TI - De Novo Computational Design of Retro-Aldol Enzymes JF - Science VL - 319 IS - 5868 SP - 1387 EP - 1391 N2 - The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model. 10.1126/science.1152692 KW - design KW - prediction KW - protein AU - Jiang, Lin AU - Althoff, Eric AU - Clemente, Fernando AU - Doyle, Lindsey AU - Rothlisberger, Daniela AU - Zanghellini, Alexandre AU - Gallaher, Jasmine AU - Betker, Jamie AU - Tanaka, Fujie AU - Barbas, Carlos AU - Hilvert, Donald AU - Houk, Kendall AU - Stoddard, Barry AU - Baker, David PY - 2008/03/07/ UR - http://dx.doi.org/10.1126/science.1152692 ER -