ArticleProtein science : a publication of the Protein Society2019
A computational method for design of connected catalytic networks in proteins.
Article in Protein science : a publication of the Protein Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed.
- Modeling protein-small molecule conformational ensembles with PLACER.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Modeling protein-small molecule conformational ensembles with PLACER.bioRxiv : the preprint server for biology · 2025Article
- Cooperative Conformational Transitions Underpin the Activation Heat Capacity in the Temperature Dependence of Enzyme Catalysis.ACS catalysis · 2024Article
- Second-Shell Residues Contribute to Catalysis by Predominately Preorganizing the Apo State in PafA.Journal of the American Chemical Society · 2023Article
- Adenylate Kinase-Catalyzed Reactions of AMP in Pieces: Specificity for Catalysis at the Nucleoside Activator and Dianion Catalytic Sites.Biochemistry · 2022Article
- Key difference between transition state stabilization and ground state destabilization: increasing atomic charge densities before or during enzyme-substrate binding.Chemical science · 2022Article
- The road to fully programmable protein catalysis.Nature · 2022Review
- The role of streptavidin and its variants in catalysis by biotinylated secondary amines.Organic & biomolecular chemistry · 2021Article
- Opening of a cryptic pocket in β-lactamase increases penicillinase activity.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Evolution of Enzyme Function and the Development of Catalytic Efficiency: Triosephosphate Isomerase, Jeremy R. Knowles, and W. John Albery.Biochemistry · 2021Article
- Artificial Organelles: Towards Adding or Restoring Intracellular Activity.Chembiochem : a European journal of chemical biology · 2021Review
- Hydrogen-Deuterium Exchange within Adenosine Deaminase, a TIM Barrel Hydrolase, Identifies Networks for Thermal Activation of Catalysis.Journal of the American Chemical Society · 2020Article
- Enabling protein-hosted organocatalytic transformations.RSC advances · 2020Review
- A computational method for design of connected catalytic networks in proteins.Protein science : a publication of the Protein Society · 2019Article
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5 authors.
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Abstract
Computational design of new active sites has generally proceeded by geometrically defining interactions between the reaction transition state(s) and surrounding side-chain functional groups which maximize transition-state stabilization, and then searching for sites in protein scaffolds where the specified side-chain-transition-state interactions can be realized. A limitation of this approach is that the interactions between the side chains themselves are not constrained. An extensive connected hydrogen bond network involving the catalytic residues was observed in a designed retroaldolase following directed evolution. Such connected networks could increase catalytic activity by preorganizing active site residues in catalytically competent orientations, and enabling concerted interactions between side chains during catalysis, for example, proton shuffling. We developed a method for designing active sites in which the catalytic side chains, in addition to making interactions with the transition state, are also involved in extensive hydrogen bond networks. Because of the added constraint of hydrogen-bond connectivity between the catalytic side chains, to find solutions, a wider range of interactions between these side chains and the transition state must be considered. Our new method starts from a ChemDraw-like two-dimensional representation of the transition state with hydrogen-bond donors, acceptors, and covalent interaction sites indicated, and all placements of side-chain functional groups that make the indicated interactions with the transition state, and are fully connected in a single hydrogen-bond network are systematically enumerated. The RosettaMatch method can then be used to identify realizations of these fully-connected active sites in protein scaffolds. The method generates many fully-connected active site solutions for a set of model reactions that are promising starting points for the design of fully-preorganized enzyme catalysts.
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