ArticleProceedings of the National Academy of Sciences of the United States of America2013
Unraveling the role of protein dynamics in dihydrofolate reductase catalysis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Who cites it
63 citing papers in PubMed.
- Transitioning enzyme catalysis towards photocatalysis.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2025Review
- Bioinformatic discovery of type 11 secretion system (T11SS) cargo across theMicrobial genomics · 2025Article
- CHARMM-GUI QM/MM Interfacer for a Quantum Mechanical and Molecular Mechanical (QM/MM) Simulation Setup: 1. Semiempirical Methods.Journal of chemical theory and computation · 2024Article
- Secondary Amine Catalysis in Enzyme Design: Broadening Protein Template Diversity through Genetic Code Expansion.Angewandte Chemie (International ed. in English) · 2024Article
- Allosteric activation unveils protein-mass modulation of ATP phosphoribosyltransferase product release.Communications chemistry · 2024Article
- Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry.Protein science : a publication of the Protein Society · 2023Article
- Profiling Enzyme Activity of l-Asparaginase II by NMR-Based Methyl Fingerprinting at Natural Abundance.Journal of the American Chemical Society · 2023Article
- Modeling Ensembles of Enzyme Reaction Pathways with Hi-MSM Reveals the Importance of Accounting for Pathway Diversity.The journal of physical chemistry. B · 2022Article
- Comparison of the Role of Protein Dynamics in Catalysis by Dihydrofolate Reductase fromThe journal of physical chemistry. B · 2022Article
- Single-Molecule Sampling of Dihydrofolate Reductase Shows Kinetic Pauses and an Endosteric Effect Linked to Catalysis.ACS catalysis · 2022Article
- Evolution of Optimized Hydride Transfer Reaction and Overall Enzyme Turnover in Human Dihydrofolate Reductase.Biochemistry · 2021Article
- Chemical Mapping Exposes the Importance of Active Site Interactions in Governing the Temperature Dependence of Enzyme Turnover.ACS catalysis · 2021Article
- Inverse heavy enzyme isotope effects in methylthioadenosine nucleosidases.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Role of Active Site Loop Dynamics in Mediating Ligand Release fromBiochemistry · 2021Article
- Cryo-kinetics Reveal Dynamic Effects on the Chemistry of Human Dihydrofolate Reductase.Chembiochem : a European journal of chemical biology · 2021Article
- Capturing the Catalytic Proton of Dihydrofolate Reductase: Implications for General Acid-Base Catalysis.ACS catalysis · 2021Article
- Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics.eLife · 2021Article
- Temperature-Dependent Kinetic Isotope Effects in R67 Dihydrofolate Reductase from Path-Integral Simulations.The journal of physical chemistry. B · 2021Article
- Protein Mass-Modulated Effects in Alkaline Phosphatase.Biochemistry · 2021Article
- The Energetic Origin of Different Catalytic Activities in Temperature-Adapted Trypsins.ACS omega · 2020Article
3 more citing papers are in PubMed but not listed here.
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11 authors.
Funding
Abstract
Protein dynamics have controversially been proposed to be at the heart of enzyme catalysis, but identification and analysis of dynamical effects in enzyme-catalyzed reactions have proved very challenging. Here, we tackle this question by comparing an enzyme with its heavy ((15)N, (13)C, (2)H substituted) counterpart, providing a subtle probe of dynamics. The crucial hydride transfer step of the reaction (the chemical step) occurs more slowly in the heavy enzyme. A combination of experimental results, quantum mechanics/molecular mechanics simulations, and theoretical analyses identify the origins of the observed differences in reactivity. The generally slightly slower reaction in the heavy enzyme reflects differences in environmental coupling to the hydride transfer step. Importantly, the barrier and contribution of quantum tunneling are not affected, indicating no significant role for "promoting motions" in driving tunneling or modulating the barrier. The chemical step is slower in the heavy enzyme because protein motions coupled to the reaction coordinate are slower. The fact that the heavy enzyme is only slightly less active than its light counterpart shows that protein dynamics have a small, but measurable, effect on the chemical reaction rate.
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