ArticleScience (New York, N.Y.)2020
How directed evolution reshapes the energy landscape in an enzyme to boost catalysis.
Article in Science (New York, N.Y.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed.
- Modulating thermal folded stability and catalytic activity of aRSC advances · 2026Article
- 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
- A sequence motif enables widespread use of noncanonical redox cofactors in natural enzymes.Nature chemical biology · 2026Article
- Enhancing Enzyme Activity Via Noncovalent Association with DNA-Functionalized Nanoparticles.JACS Au · 2026Article
- Substrate-Specific Differences in Catalytic Strategy and Activity across Ketol-Acid Reductoisomerase Variants.The journal of physical chemistry. B · 2026Article
- Density Functional Theory Charge Delocalization Error Determines Computed Activation Barriers in Enzymatic Kemp Elimination.Chembiochem : a European journal of chemical biology · 2026Article
- Zero-shot design of abioRxiv : the preprint server for biology · 2026Article
- How far can you go? Extrapolating values of catalytic activity from known protein landscapes in natural and directed evolution.Chemical Society reviews · 2026Review
- Single-molecule kinetic exploration of functional sub-states in an evolving phosphotriesterase.Nature communications · 2026Article
- Comparative Review of Microbial Chitosanases: Properties, Structures, Hydrolytic Modes and Applications.Current microbiology · 2026Review
- Decoding the substrate specificity landscape of a promiscuous enzyme through multi-substrate mutational scanning.Nature communications · 2026Article
- Article
- Hydrogen-deuterium exchange reveals catalytically linked protein flexibility in myoglobin-mediated intramolecular C(spProtein science : a publication of the Protein Society · 2026Article
- Towards patient-relevant structures: reviewing body-temperature biological macromolecules and their ligands for pharmaceutical applications.Acta crystallographica. Section D, Structural biology · 2026Review
- Phosphate ions modulate enzyme activity and epistatic effects in two clavulanic acid-resistant β-lactamase mutants.Protein science : a publication of the Protein Society · 2025Article
- Directed evolution of a beta-lactamase samples a wide variety of conformational states.Protein science : a publication of the Protein Society · 2025Article
- Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release.Nature communications · 2025Article
- Article
- Highly efficient enzymes designed from scratch.Nature · 2025Article
- Drug resistance and tumor heterogeneity: cells and ensembles.Biophysical reviews · 2025Review
24 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
The advent of biocatalysts designed computationally and optimized by laboratory evolution provides an opportunity to explore molecular strategies for augmenting catalytic function. Applying a suite of nuclear magnetic resonance, crystallography, and stopped-flow techniques to an enzyme designed for an elementary proton transfer reaction, we show how directed evolution gradually altered the conformational ensemble of the protein scaffold to populate a narrow, highly active conformational ensemble and accelerate this transformation by nearly nine orders of magnitude. Mutations acquired during optimization enabled global conformational changes, including high-energy backbone rearrangements, that cooperatively organized the catalytic base and oxyanion stabilizer, thus perfecting transition-state stabilization. The development of protein catalysts for many chemical transformations could be facilitated by explicitly sampling conformational substates during design and specifically stabilizing productive substates over all unproductive conformations.
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Registered trials
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.