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

TitleComputational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction
Publication TypeJournal Article
Year of Publication2010
AuthorsSiegel, 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 Published2010 Jul 16
KeywordsAcrylamides, 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.

Alternate JournalScience
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