Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction.

Publication Type:

Journal Article


Science (New York, N.Y.), Volume 329, Issue 5989, p.309-13 (2010)


2010, Acrylamides, Algorithms, Basic Sciences Division, Butadienes, Carbon, CATALYSIS, CATALYTIC DOMAIN, Center-Authored Paper, Computer Simulation, Computer-Aided Design, Crystallography, X-Ray, Enzymes, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Kinetics, Models, Molecular, mutagenesis, Physicochemical Processes, Protein Conformation, Protein Engineering, PROTEINS, Software, Stereoisomerism, Substrate Specificity


The Diels-Alder reaction is a cornerstone in organic synthesis, forming two carbon-carbon bonds and up to four new stereogenic centers in one step. No naturally occurring enzymes have been shown to catalyze bimolecular Diels-Alder reactions. We describe the de novo computational design and experimental characterization of enzymes catalyzing a bimolecular Diels-Alder reaction with high stereoselectivity and substrate specificity. X-ray crystallography confirms that the structure matches the design for the most active of the enzymes, and binding site substitutions reprogram the substrate specificity. Designed stereoselective catalysts for carbon-carbon bond-forming reactions should be broadly useful in synthetic chemistry.