ArticleJournal of the American Chemical Society2014
Extension and limits of the network of coupled motions correlated to hydride transfer in dihydrofolate reductase.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Donor-Acceptor Separation Augments Temperature Dependence of Kinetic Isotope Effects in NADH Model Hydride Transfer Reactions: Mimicking Enzyme versus Mutant Dynamics.The journal of physical chemistry. B · 2026Article
- Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase.The journal of physical chemistry. B · 2024Article
- Statistical Coupling Analysis Predicts Correlated Motions in Dihydrofolate Reductase.bioRxiv : the preprint server for biology · 2024Article
- Perturbative diffraction methods resolve a conformational switch that facilitates a two-step enzymatic mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Hydride Transfer Mechanism of Enzymatic Sugar Nucleotide C2 Epimerization Probed with a Loose-Fit CDP-Glucose Substrate.ACS catalysis · 2022Article
- Evolution of Optimized Hydride Transfer Reaction and Overall Enzyme Turnover in Human Dihydrofolate Reductase.Biochemistry · 2021Article
- Effects of Distal Mutations on Ligand-Binding Affinity inACS omega · 2021Article
- Temperature-Dependent Kinetic Isotope Effects in R67 Dihydrofolate Reductase from Path-Integral Simulations.The journal of physical chemistry. B · 2021Article
- Acceleration of catalysis in dihydrofolate reductase by transient, site-specific photothermal excitation.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Oscillatory Active-site Motions Correlate with Kinetic Isotope Effects in Formate Dehydrogenase.ACS catalysis · 2019Article
- Article
- Biophysical Characterization of a Disabled Double Mutant of Soybean Lipoxygenase: The "Undoing" of Precise Substrate Positioning Relative to Metal Cofactor and an Identified Dynamical Network.Journal of the American Chemical Society · 2019Article
- Experimental and Computational Studies Delineate the Role of Asparagine 177 in Hydride Transfer for E. coli Thymidylate Synthase.ACS catalysis · 2018Article
- Conformational dynamics and enzyme evolution.Journal of the Royal Society, Interface · 2018Review
- Engineered control of enzyme structural dynamics and function.Protein science : a publication of the Protein Society · 2018Review
- Contribution of buried distal amino acid residues in horse liver alcohol dehydrogenase to structure and catalysis.Protein science : a publication of the Protein Society · 2018Article
- Protein Mass Effects on Formate Dehydrogenase.Journal of the American Chemical Society · 2017Article
- Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.Journal of chemical theory and computation · 2017Article
- Mechanistic and Evolutionary Insights from Comparative Enzymology of Phosphomonoesterases and Phosphodiesterases across the Alkaline Phosphatase Superfamily.Journal of the American Chemical Society · 2016Article
- Article
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Authors and funding
4 authors.
Funding
Abstract
Enzyme catalysis has been studied extensively, but the role of enzyme dynamics in the catalyzed chemical conversion is still an enigma. The enzyme dihydrofolate reductase (DHFR) is often used as a model system to assess a network of coupled motions across the protein that may affect the catalyzed chemical transformation. Molecular dynamics simulations, quantum mechanical/molecular mechanical studies, and bioinformatics studies have suggested the presence of a "global dynamic network" of residues in DHFR. Earlier studies of two DHFR distal mutants, G121V and M42W, indicated that these residues affect the chemical step synergistically. While this finding was in accordance with the concept of a network of functional motions across the protein, two residues do not constitute a network. To better define the extent and limits of the proposed network, the current work studied two remote residues predicted to be part of the same network: W133 and F125. The effect of mutations in these residues on the nature of the chemical step was examined via measurements of the temperature-dependence of the intrinsic kinetic isotope effects (KIEs) and other kinetic parameters, and double mutants were used to tie the findings to G121 and M42. The findings indicate that residue F125, which was implicated by both calculations and bioinformatic methods, is a part of the same global dynamic network as G121 and M42, while W133, implicated only by bioinformatics, is not. These findings extend our understanding of the proposed network and the relations between functional and genomic couplings. Delineating that network illuminates the need to consider remote residues and protein structural dynamics in the rational design of drugs and of biomimetic catalysts.
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