ArticleProceedings of the National Academy of Sciences of the United States of America2012
Iterative approach to computational enzyme design.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 133 papers.
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133 citing papers in PubMed, 335 citations in OpenAlex.
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- Multistate Enzyme Design Enables Efficient and Stereoselective Multistep Catalysis.bioRxiv : the preprint server for biology · 2026Article
- Density Functional Theory Charge Delocalization Error Determines Computed Activation Barriers in Enzymatic Kemp Elimination.Chembiochem : a European journal of chemical biology · 2026Article
- Emergence of specific binding and catalysis from a designed generalist binding protein.Nature chemistry · 2026Article
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- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
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- Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release.Nature communications · 2025Article
- Enzyme miniaturization: Revolutionizing future biocatalysts.Biotechnology advances · 2025Review
- Continuous Nicotine Monitors for Personal Nicotine Pharmacokinetics: A Receptor-Aware Research Agenda.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2025Review
- Highly efficient enzymes designed from scratch.Nature · 2025Article
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- Computational design of serine hydrolases.Science (New York, N.Y.) · 2025Article
- Physics-based modeling in the new era of enzyme engineering.Nature computational science · 2025Review
- Robust enzyme discovery and engineering with deep learning using CataPro.Nature communications · 2025Article
- Enriching productive mutational paths accelerates enzyme evolution.Nature chemical biology · 2024Article
73 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
A general approach for the computational design of enzymes to catalyze arbitrary reactions is a goal at the forefront of the field of protein design. Recently, computationally designed enzymes have been produced for three chemical reactions through the synthesis and screening of a large number of variants. Here, we present an iterative approach that has led to the development of the most catalytically efficient computationally designed enzyme for the Kemp elimination to date. Previously established computational techniques were used to generate an initial design, HG-1, which was catalytically inactive. Analysis of HG-1 with molecular dynamics simulations (MD) and X-ray crystallography indicated that the inactivity might be due to bound waters and high flexibility of residues within the active site. This analysis guided changes to our design procedure, moved the design deeper into the interior of the protein, and resulted in an active Kemp eliminase, HG-2. The cocrystal structure of this enzyme with a transition state analog (TSA) revealed that the TSA was bound in the active site, interacted with the intended catalytic base in a catalytically relevant manner, but was flipped relative to the design model. MD analysis of HG-2 led to an additional point mutation, HG-3, that produced a further threefold improvement in activity. This iterative approach to computational enzyme design, including detailed MD and structural analysis of both active and inactive designs, promises a more complete understanding of the underlying principles of enzymatic catalysis and furthers progress toward reliably producing active enzymes.
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