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

Justin B Siegel, Alexandre Zanghellini, Helena M Lovick, Gert Kiss, Abigail R Lambert, Jennifer L St Clair, Jasmine L Gallaher, Donald Hilvert, Michael H Gelb, Barry L Stoddard, Kendall N Houk, Forrest E Michael, David Baker

Index: Science 329(5989) , 309-13, (2010)

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Abstract

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.