ArticleJournal of the American Chemical Society2019
Protein Flexibility and Stiffness Enable Efficient Enzymatic Catalysis.
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 88 papers.
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Who cites it
88 citing papers in PubMed.
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- Formate Dehydrogenase: The Role of the AMP Cofactor Fragment in Stabilization of the Transition State for Enzyme-Catalyzed Hydride Transfer.ACS omega · 2026Article
- Hydrophobic interactions of a substrate with L193 on the flexible substrate-binding loop contribute to 3α-hydroxysteroid dehydrogenase/carbonyl reductase catalytic efficiency.Protein science : a publication of the Protein Society · 2026Article
- A dual catalytic architecture promotes C-2 stereoinversion of CDP-glucose by the CDP-tyvelose 2-epimerase from Thermodesulfatator atlanticus.The Journal of biological chemistry · 2026Article
- Temperature-Dependent Active-Site Rearrangements of PETaseSM14: Insights from Molecular Dynamics Simulations.International journal of molecular sciences · 2026Article
- Binding Site Vectors Enable Mapping of Cytochrome P450 Functional Landscapes.Journal of chemical information and modeling · 2026Article
- Changes in Water Dynamics by Osmolytes Regulate Enzyme Activity.The journal of physical chemistry. B · 2026Article
- The Role of Protein Side Chains in Enzyme-Activating Conformational Changes: Lessons from Studies on Variant Enzymes.Chemical reviews · 2025Review
- Enzyme Architecture: Activation of Phosphite Dehydrogenase-Catalyzed Hydride Transfer by NADBiochemistry · 2025Article
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- Structural and biochemical basis for cannabinoid cyclase activity in marine bacterial flavoenzymes.bioRxiv : the preprint server for biology · 2025Article
- Bifunctional Catalysis of Aldol Reactions by Foldamer Dihydrazides: Assessment of Conformational Preorganization.Journal of the American Chemical Society · 2025Article
- Endohedral Coordination of Bulky Substrates in Metalloenzyme-Like Organometallic Nanotubes.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Exploring the Evolution-Coupling Hypothesis: Do Enzymes' Performance Gains Correlate with Increased Dissipation?Entropy (Basel, Switzerland) · 2025Article
28 more citing papers are in PubMed but not listed here.
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1 author.
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Abstract
The enormous rate accelerations observed for many enzyme catalysts are due to strong stabilizing interactions between the protein and reaction transition state. The defining property of these catalysts is their specificity for binding the transition state with a much higher affinity than substrate. Experimental results are presented which show that the phosphodianion-binding energy of phosphate monoester substrates is used to drive conversion of their protein catalysts from flexible and entropically rich ground states to stiff and catalytically active Michaelis complexes. These results are generalized to other enzyme-catalyzed reactions. The existence of many enzymes in flexible, entropically rich, and inactive ground states provides a mechanism for utilization of ligand-binding energy to mold these catalysts into stiff and active forms. This reduces the substrate-binding energy expressed at the Michaelis complex, while enabling the full and specific expression of large transition-state binding energies. Evidence is presented that the complexity of enzyme conformational changes increases with increases in the enzymatic rate acceleration. The requirement that a large fraction of the total substrate-binding energy be utilized to drive conformational changes of floppy enzymes is proposed to favor the selection and evolution of protein folds with multiple flexible unstructured loops, such as the TIM-barrel fold. The effect of protein motions on the kinetic parameters for enzymes that undergo ligand-driven conformational changes is considered. The results of computational studies to model the complex ligand-driven conformational change in catalysis by triosephosphate isomerase are presented.
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