ArticleJournal of the American Chemical Society2019
Optimization of the Turnover in Artificial Enzymes via Directed Evolution Results in the Coupling of Protein Dynamics to Chemistry.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Predicting Activation Barriers With Ring and Bond Critical Points in the Kemp Elimination Reaction.Chemphyschem : a European journal of chemical physics and physical chemistry · 2026Article
- Substrate-Specific Differences in Catalytic Strategy and Activity across Ketol-Acid Reductoisomerase Variants.The journal of physical chemistry. B · 2026Article
- Fast Motions in 5 Alpha Reductase and Its Impact on Enzyme Kinetics.ACS catalysis · 2026Article
- Directed Evolution of a Modular Polyketide Synthase Thioesterase for Generation of a Hybrid Macrocyclic Ring System.ACS catalysis · 2025Article
- Article
- Chlorophyllase fromACS bio & med chem Au · 2024Article
- Transition Path Sampling Based Free Energy Calculations of Evolution's Effect on Rates in β-Lactamase: The Contributions of Rapid Protein Dynamics to Rate.The journal of physical chemistry. B · 2024Article
- The Evolution of the Acylation Mechanism inACS catalysis · 2024Article
- Substrate Turnover Dynamics Guide Ketol-Acid Reductoisomerase Redesign for Increased Specific Activity.ACS catalysis · 2024Article
- Structural, Spectroscopic, and Computational Insights from Canavanine-Bound and Two Catalytically Compromised Variants of the Ethylene-Forming Enzyme.Biochemistry · 2024Article
- Transition Path Sampling Study of Engineered Enzymes That Catalyze the Morita-Baylis-Hillman Reaction: Why Is Enzyme Design so Difficult?Journal of chemical information and modeling · 2024Article
- Custom tuning of Rieske oxygenase reactivity.Nature communications · 2023Article
- Going Full Circle with Organocatalysis and Biocatalysis: The Latent Potential of Cofactor Mimics in Asymmetric Synthesis.The Journal of organic chemistry · 2023Review
- Protein Dynamics and Enzymatic Catalysis.The journal of physical chemistry. B · 2023Review
- Atomistic description of the relationship between protein dynamics and catalysis with transition path sampling.Methods in enzymology · 2023Review
- Perspective: Path Sampling Methods Applied to Enzymatic Catalysis.Journal of chemical theory and computation · 2022Review
- Article
- Transition Path Sampling Based Calculations of Free Energies for Enzymatic Reactions: The Case of Human Methionine Adenosyl Transferase andThe journal of physical chemistry. B · 2022Article
- Method for Identifying Common Features in Reactive Trajectories of a Transition Path Sampling Ensemble.Journal of chemical theory and computation · 2022Article
- Engineered Tryptophan Synthase Balances Equilibrium Effects and Fast Dynamic Effects.ACS catalysis · 2022Article
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4 authors.
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Abstract
The design of artificial enzymes is an emerging field of research. Although progress has been made, the catalytic proficiency of many designed enzymes is low compared to natural enzymes. Nevertheless, recently Hilvert et al. ( Nat. Chem. 2017, 9, 50-56) created a series of five artificial retro-aldolase enzymes via directed evolution, with the final variant exhibiting a rate comparable to the naturally occurring enzyme fructose 1,6 bisphosphate aldolase. We present a study of this system in atomistic detail that elucidates the effects of mutational changes on the chemical step. Transition path sampling is used to create ensembles of reactive trajectories, and committor analysis is used to identify the stochastic separatrix of each ensemble. The application of committor distribution analysis to constrained trajectories allows the identification of changes in important protein motions coupled to reaction across the generated series of the artificial retro-aldolases. We observed two different reaction mechanisms and analyzed the role of the residues participating in the reaction coordinate of each enzyme. However, only in the most evolved variant we identified a fast motion that promotes catalysis, suggesting that this rate promoting vibration was introduced during directed evolution. This study provides further evidence that protein dynamics must be taken into account in designing efficient artificial enzymes.
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