ArticleJournal of the American Chemical Society2016
Substrate and Transition State Binding in Alkaline Phosphatase Analyzed by Computation of Oxygen Isotope Effects.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Force fields matter in DNA polProtein science : a publication of the Protein Society · 2026Article
- Article
- Oxygen Isotope Analyses of Phosphate and Organophosphorus Compounds by Electrospray Ionization Orbitrap Mass Spectrometry.Analytical chemistry · 2025Article
- Article
- CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.The journal of physical chemistry. B · 2024Review
- Second-Shell Residues Contribute to Catalysis by Predominately Preorganizing the Apo State in PafA.Journal of the American Chemical Society · 2023Article
- Hybrid Quantum Mechanical/Molecular Mechanical Methods For Studying Energy Transduction in Biomolecular Machines.Annual review of biophysics · 2023Review
- Factors That Determine the Variation of Equilibrium and Kinetic Properties of QM/MM Enzyme Simulations: QM Region, Conformation, and Boundary Condition.Journal of chemical theory and computation · 2022Article
- What Does the Brønsted Slope Measure in the Phosphoryl Transfer Transition State?ACS catalysis · 2020Article
- Differences in the Nature of the Phosphoryl Transfer Transition State in Protein Phosphatase 1 and Alkaline Phosphatase: Insights from QM Cluster Models.The journal of physical chemistry. B · 2020Article
- Single-step Replacement of an Unreactive C-H Bond by a C-S Bond Using Polysulfide as the Direct Sulfur Source in Anaerobic Ergothioneine Biosynthesis.ACS catalysis · 2020Article
- Examining the Mechanism of Phosphite Dehydrogenase with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.Biochemistry · 2020Article
- Extensive free-energy simulations identify water as the base in nucleotide addition by DNA polymerase.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Unraveling mechanisms of the uncoordinated nucleophiles: theoretical elucidations of the cleavage of bis(RSC advances · 2019Article
- Two symmetric arginine residues play distinct roles inProceedings of the National Academy of Sciences of the United States of America · 2019Article
- Article
- Structural and mechanistic basis for preferential deadenylation of U6 snRNA by Usb1.Nucleic acids research · 2018Article
- Analysis of Phosphoryl-Transfer Enzymes with QM/MM Free Energy Simulations.Methods in enzymology · 2018Article
- Regulation and Plasticity of Catalysis in Enzymes: Insights from Analysis of Mechanochemical Coupling in Myosin.Biochemistry · 2017Article
- Perspective: Quantum mechanical methods in biochemistry and biophysics.The Journal of chemical physics · 2016Article
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2 authors.
Funding
Abstract
Enzymes are powerful catalysts, and a thorough understanding of the sources of their catalytic power will facilitate many medical and industrial applications. Here we have studied the catalytic mechanism of alkaline phosphatase (AP), which is one of the most catalytically proficient enzymes known. We have used quantum mechanics calculations and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to model a variety of isotope effects relevant to the reaction of AP. We have calculated equilibrium isotope effects (EIEs), binding isotope effects (BIEs), and kinetic isotope effects (KIEs) for a range of phosphate mono- and diester substrates. The results agree well with experimental values, but the model for the reaction's transition state (TS) differs from the original interpretation of those experiments. Our model indicates that isotope effects on binding make important contributions to measured KIEs on V/K, which complicated interpretation of the measured values. Our results provide a detailed interpretation of the measured isotope effects and make predictions that can test the proposed model. The model indicates that the substrate is deformed in the ground state (GS) of the reaction and partially resembles the TS. The highly preorganized active site preferentially binds conformations that resemble the TS and not the GS, which induces the substrate to adapt to the enzyme, rather than the other way around-as with classic "induced fit" models. The preferential stabilization of the TS over the GS is what lowers the barrier to the chemical step.
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