ArticleProceedings of the National Academy of Sciences of the United States of America2010
Exploring challenges in rational enzyme design by simulating the catalysis in artificial kemp eliminase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
- Bridging Algorithms and Biocatalysis: Perspectives on AI-Supported Enzyme Engineering.Molecules (Basel, Switzerland) · 2026Review
- MAPLE: a machine-learning force-field-native platform for automated reaction modeling and enzyme design.Chemical science · 2026Article
- Emergence of specific binding and catalysis from a designed generalist binding protein.Nature chemistry · 2026Article
- Of Revolutions and Roadblocks: The Emerging Role of Machine Learning in Biocatalysis.ACS central science · 2025Review
- A Three-Module Machine Learning Framework for Protein Sequence- and Temperature-DependentACS synthetic biology · 2025Article
- Article
- Enzyme Enhancement Through Computational Stability Design Targeting NMR-Determined Catalytic Hotspots.Journal of the American Chemical Society · 2025Article
- Computational design of serine hydrolases.Science (New York, N.Y.) · 2025Article
- Investigation of Electrostatic Effects on Enyzme Catalysis: Insights from Computational Simulations of Monoamine Oxidase A Pathological Variants Leading to the Brunner Syndrome.Journal of chemical information and modeling · 2025Article
- Computational design of serine hydrolases.bioRxiv : the preprint server for biology · 2024Article
- Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction.Scientific reports · 2022Article
- Natural Evolution Provides Strong Hints about Laboratory Evolution of Designer Enzymes.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The road to fully programmable protein catalysis.Nature · 2022Review
- Catalytic Principles from Natural Enzymes and Translational Design Strategies for Synthetic Catalysts.ACS central science · 2021Review
- The Energetic Origin of Different Catalytic Activities in Temperature-Adapted Trypsins.ACS omega · 2020Article
- Enhancing aChemical science · 2020Article
- Bottom-Up Nonempirical Approach To Reducing Search Space in Enzyme Design Guided by Catalytic Fields.Journal of chemical theory and computation · 2020Article
- Article
- Exploring the challenges of computational enzyme design by rebuilding the active site of a dehalogenase.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The evolution of multiple active site configurations in a designed enzyme.Nature communications · 2018Article
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Authors and funding
4 authors.
Funding
Abstract
One of the fundamental challenges in biotechnology and in biochemistry is the ability to design effective enzymes. Doing so would be a convincing manifestation of a full understanding of the origin of enzyme catalysis. Despite an impressive progress, most of the advances on this front have been made by placing the reacting fragments in the proper places, rather than by optimizing the environment preorganization, which is the key factor in enzyme catalysis. Rational improvement of the preorganization would require approaches capable of evaluating reliably the actual catalytic effect. This work takes previously designed kemp eliminases as a benchmark for a computer aided enzyme design, using the empirical valence bond as the main screening tool. The observed absolute catalytic effect and the effect of directed evolution are reproduced and analyzed (assuming that the substrate is in the designed site). It is found that, in the case of kemp eliminases, the transition state charge distribution makes it hard to exploit the active site polarity, even with the ability to quantify the effect of different mutations. Unexpectedly, it is found that the directed evolution mutants lead to the reduction of solvation of the reactant state by water molecules rather that to the more common mode of transition state stabilization used by naturally evolved enzymes. Finally it is pointed out that our difficulties in improving Kemp eliminase are not due to overlooking exotic effect, but to the challenge in designing a preorganized environment that would exploit the small change it charge distribution during the formation of the transition state.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.