Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction
|Title||Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction|
|Publication Type||Journal Article|
|Year of Publication||2010|
|Authors||Siegel, J. B., Zanghellini A., Lovick H. M., Kiss G., Lambert A. R., St Clair J. L., Gallaher J. L., Hilvert D., Gelb M. H., Stoddard B. L., Houk K. N., Michael F. E., & Baker D.|
|Date Published||2010 Jul 16|
|Keywords||Acrylamides, Algorithms, Butadienes, Carbon, Catalysis, Catalytic Domain, Computer Simulation, Computer-Aided Design, Crystallography, X-Ray, Enzymes, Hydrogen Bonding, Hydrophobicity, Kinetics, Models, Molecular, Mutagenesis, Physicochemical Processes, Primary Publication, 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.