ArticleJournal of the American Chemical Society2012
Computational design of catalytic dyads and oxyanion holes for ester hydrolysis.
Article in Journal of the American Chemical Society, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers.
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Who cites it
65 citing papers in PubMed.
- High-throughput Optical Analysis to Inform Design of Electrochemical Biosensors.ACS measurement science au · 2026Review
- Structure-activity relationships in catalytic amyloids.Journal of inorganic biochemistry · 2026Article
- Protein engineering: status report.Protein engineering, design & selection : PEDS · 2026Review
- Protein-confined imidazolium intermediates enable diverse biocatalytic C-C and C-N bond formations.Nature catalysis · 2026Article
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- Atom-level enzyme active site scaffolding using RFdiffusion2.Nature methods · 2026Article
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- Enzyme miniaturization: Revolutionizing future biocatalysts.Biotechnology advances · 2025Review
- SubTuner leverages physics-based modeling to complement AI in enzyme engineering toward non-native substrates.Chem catalysis · 2025Article
- Computational design of serine hydrolases.Science (New York, N.Y.) · 2025Article
- Computational and biochemical characterization of the immobilized esterase of Salinicoccus roseus for pesticide degradation.Scientific reports · 2024Article
- Structure-based clustering and mutagenesis of bacterial tannases reveals the importance and diversity of active site-capping domains.Protein science : a publication of the Protein Society · 2024Article
- Spiers Memorial Lecture: Engineering biocatalysts.Faraday discussions · 2024Article
- Computational design of serine hydrolases.bioRxiv : the preprint server for biology · 2024Article
- Noncanonical Amino Acids in Biocatalysis.Chemical reviews · 2024Review
- Genetically encoded Nδ-vinyl histidine for the evolution of enzyme catalytic center.Nature communications · 2024Article
- A non-canonical nucleophile unlocks a new mechanistic pathway in a designed enzyme.Nature communications · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Hydrolase mimic via second coordination sphere engineering in metal-organic frameworks for environmental remediation.Nature communications · 2023Article
- EnzyHTP Computational Directed Evolution with Adaptive Resource Allocation.Journal of chemical information and modeling · 2023Article
5 more citing papers are in PubMed but not listed here.
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23 authors.
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Abstract
Nucleophilic catalysis is a general strategy for accelerating ester and amide hydrolysis. In natural active sites, nucleophilic elements such as catalytic dyads and triads are usually paired with oxyanion holes for substrate activation, but it is difficult to parse out the independent contributions of these elements or to understand how they emerged in the course of evolution. Here we explore the minimal requirements for esterase activity by computationally designing artificial catalysts using catalytic dyads and oxyanion holes. We found much higher success rates using designed oxyanion holes formed by backbone NH groups rather than by side chains or bridging water molecules and obtained four active designs in different scaffolds by combining this motif with a Cys-His dyad. Following active site optimization, the most active of the variants exhibited a catalytic efficiency (k(cat)/K(M)) of 400 M(-1) s(-1) for the cleavage of a p-nitrophenyl ester. Kinetic experiments indicate that the active site cysteines are rapidly acylated as programmed by design, but the subsequent slow hydrolysis of the acyl-enzyme intermediate limits overall catalytic efficiency. Moreover, the Cys-His dyads are not properly formed in crystal structures of the designed enzymes. These results highlight the challenges that computational design must overcome to achieve high levels of activity.
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