Enantioselective Enzymes by Computational Design and In Silico Screening

Hein J Wijma, Robert J Floor, Sinisa Bjelic, Siewert J Marrink, David Baker, Dick B Janssen

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Computational enzyme design holds great promise for providing new biocatalysts for synthetic chemistry. A strategy to design small mutant libraries of complementary enantioselective epoxide hydrolase variants for the production of highly enantioenriched (S,S)-diols and (R,R)-diols is developed. Key features of this strategy (CASCO, catalytic selectivity by computational design) are the design of mutations that favor binding of the substrate in a predefined orientation, the introduction of steric hindrance to prevent unwanted substrate binding modes, and ranking of designs by high-throughput molecular dynamics simulations. Using this strategy we obtained highly stereoselective mutants of limonene epoxide hydrolase after experimental screening of only 37 variants. The results indicate that computational methods can replace a substantial amount of laboratory work when developing enantioselective enzymes.

Original languageEnglish
Pages (from-to)3726-3730
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number12
Early online date4-Feb-2015
Publication statusPublished - 16-Mar-2015

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