ArticleProtein science : a publication of the Protein Society2007
Conformational change of the methionine 20 loop of Escherichia coli dihydrofolate reductase modulates pKa of the bound dihydrofolate.
Article in Protein science : a publication of the Protein Society, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- Capturing the Catalytic Proton of Dihydrofolate Reductase: Implications for General Acid-Base Catalysis.ACS catalysis · 2021Article
- Temperature-Dependent Kinetic Isotope Effects in R67 Dihydrofolate Reductase from Path-Integral Simulations.The journal of physical chemistry. B · 2021Article
- Electric Field Measurements Reveal the Pivotal Role of Cofactor-Substrate Interaction in Dihydrofolate Reductase Catalysis.ACS catalysis · 2020Article
- DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents.Molecules (Basel, Switzerland) · 2019Review
- Biliverdin Reductase B Dynamics Are Coupled to Coenzyme Binding.Journal of molecular biology · 2018Article
- Modulating Enzyme Activity by Altering Protein Dynamics with Solvent.Biochemistry · 2018Article
- The role of the MetThe Journal of biological chemistry · 2017Article
- Perspectives on electrostatics and conformational motions in enzyme catalysis.Accounts of chemical research · 2015Review
- Toward resolving the catalytic mechanism of dihydrofolate reductase using neutron and ultrahigh-resolution X-ray crystallography.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Escherichia coli dihydrofolate reductase catalyzed proton and hydride transfers: temporal order and the roles of Asp27 and Tyr100.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Preliminary joint X-ray and neutron protein crystallographic studies of ecDHFR complexed with folate and NADP+.Acta crystallographica. Section F, Structural biology communications · 2014Article
- Increased dynamic effects in a catalytically compromised variant of Escherichia coli dihydrofolate reductase.Journal of the American Chemical Society · 2013Article
- Connecting protein conformational dynamics with catalytic function as illustrated in dihydrofolate reductase.Biochemistry · 2013Article
- Multiple intermediates, diverse conformations, and cooperative conformational changes underlie the catalytic hydride transfer reaction of dihydrofolate reductase.Topics in current chemistry · 2013Review
- Effects of the donor-acceptor distance and dynamics on hydride tunneling in the dihydrofolate reductase catalyzed reaction.Journal of the American Chemical Society · 2012Article
- Constant pH Molecular Dynamics Simulations of Nucleic Acids in Explicit Solvent.Journal of chemical theory and computation · 2012Article
- A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis.Science (New York, N.Y.) · 2011Article
- Conformational dependence of 13C shielding and coupling constants for methionine methyl groups.Journal of biomolecular NMR · 2010Article
- Functionally important conformations of the Met20 loop in dihydrofolate reductase are populated by rapid thermal fluctuations.Journal of the American Chemical Society · 2009Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
We evaluate the pK(a) of dihydrofolate (H(2)F) at the N(5) position in three ternary complexes with Escherichia coli dihydrofolate reductase (ecDHFR), namely ecDHFR(NADP(+):H(2)F) in the closed form (1), and the Michaelis complexes ecDHFR(NADPH:H(2)F) in the closed (2) and occluded (3) forms, by performing free energy perturbation with molecular dynamics simulations (FEP/MD). Our simulations suggest that in the Michaelis complex the pK(a) is modulated by the Met20 loop fluctuations, providing the largest pK(a) shift in substates with a "tightly closed" loop conformation; in the "partially closed/open" substates, the pK(a) is similar to that in the occluded complex. Conducive to the protonation, tightly closing the Met20 loop enhances the interactions of the cofactor and the substrate with the Met20 side chain and aligns the nicotinamide ring of the cofactor coplanar with the pterin ring of the substrate. Overall, the present study favors the hypothesis that N(5) is protonated directly from solution and provides further insights into the mechanism of the substrate protonation.
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