ArticleJournal of the American Chemical Society2009
Functionally important conformations of the Met20 loop in dihydrofolate reductase are populated by rapid thermal fluctuations.
Article in Journal of the American Chemical Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed.
- X-ray-driven chemistry and conformational heterogeneity in atomic resolution crystal structures of bacterial dihydrofolate reductases.bioRxiv : the preprint server for biology · 2023Article
- Computational Studies of Catalytic Loop Dynamics inThe journal of physical chemistry. B · 2019Article
- Article
- DHFR Inhibitors: Reading the Past for Discovering Novel Anticancer Agents.Molecules (Basel, Switzerland) · 2019Review
- A Biophysical Perspective on Enzyme Catalysis.Biochemistry · 2019Article
- Protein Conformational Transitions from All-Atom Adaptively Biased Path Optimization.Journal of chemical theory and computation · 2018Article
- High-pressure protein crystal structure analysis of Escherichia coli dihydrofolate reductase complexed with folate and NADPActa crystallographica. Section D, Structural biology · 2018Article
- Multiscale molecular dynamics simulations of rotary motor proteins.Biophysical reviews · 2018Review
- Structural and Dynamics Perspectives on the Binding of Substrate and Inhibitors in Mycobacterium tuberculosis DHFR.Scientia pharmaceutica · 2017Article
- Effects of isoleucine 135 side chain length on the cofactor donor-acceptor distance within FBiochemistry and biophysics reports · 2017Article
- Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms.Biochimica et biophysica acta · 2016Review
- Examinations of the Chemical Step in Enzyme Catalysis.Methods in enzymology · 2016Article
- Chemical Ligation and Isotope Labeling to Locate Dynamic Effects during Catalysis by Dihydrofolate Reductase.Angewandte Chemie (International ed. in English) · 2015Article
- Linking protein motion to enzyme catalysis.Molecules (Basel, Switzerland) · 2015Review
- Mechanism of the αβ conformational change in F1-ATPase after ATP hydrolysis: free-energy simulations.Biophysical journal · 2015Article
- Extension and limits of the network of coupled motions correlated to hydride transfer in dihydrofolate reductase.Journal of the American Chemical Society · 2014Article
- Multiple intermediates, diverse conformations, and cooperative conformational changes underlie the catalytic hydride transfer reaction of dihydrofolate reductase.Topics in current chemistry · 2013Review
- Hydrogen tunneling links protein dynamics to enzyme catalysis.Annual review of biochemistry · 2013Review
- Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms.Theoretical chemistry accounts · 2012Article
- Active site hydrophobic residues impact hydrogen tunneling differently in a thermophilic alcohol dehydrogenase at optimal versus nonoptimal temperatures.Biochemistry · 2012Article
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2 authors.
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Abstract
Conformational changes in enzymes are well recognized to play an important role in the organization of the reactive groups for efficient catalysis. This study reveals atomic and energetic details of the conformational change process that precedes the catalytic reaction of the enzyme dihydrofolate reductase. The computed free energy profile provides insights into the ligand binding mechanism and a quantitative estimate of barrier heights separating different conformational states along the pathway. Studies show that the ternary complex comprised of NADPH cofactor and substrate dihydrofolate undergoes transitions between a closed state and an occluded state via an intermediate "open" conformation. During these transitions the largest conformational change occurs in the Met20 loop of DHFR and is accompanied by the motion of the cofactor into and out of the binding pocket. When the cofactor is out of the binding pocket, the enzyme frequently samples open and occluded conformations with a small (approximately 5 k(B)T) free energy barrier between the two states. However, when the cofactor is in the binding pocket, the closed conformation is thermodynamically most favored. The determination of a profile characterizing the position-dependent diffusion of the Met20 loop allowed us to apply reaction rate theory and deduce the kinetics of loop motions based on the computed free energy landscape.
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