ArticleProceedings of the National Academy of Sciences of the United States of America2016
Kinetic selection vs. free energy of DNA base pairing in control of polymerase fidelity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Pol γ possesses separate metal binding sites for polymerase and strand displacement functions.Nucleic acids research · 2026Article
- Non-enzymatic error correction in self-replicators without extraneous energy supply.Scientific reports · 2026Article
- Modifying the Basicity of the dNTP Leaving Group Modulates Precatalytic Conformational Changes of DNA Polymerase β.Biochemistry · 2024Article
- Effects of error, chimera, bias, and GC content on the accuracy of amplicon sequencing.mSystems · 2023Article
- In crystallo observation of active site dynamics and transient metal ion binding within DNA polymerases.Structural dynamics (Melville, N.Y.) · 2023Article
- Watching right and wrong nucleotide insertion captures hidden polymerase fidelity checkpoints.Nature communications · 2022Article
- In crystallo observation of three metal ion promoted DNA polymerase misincorporation.Nature communications · 2022Article
- Watching a double strand break repair polymerase insert a pro-mutagenic oxidized nucleotide.Nature communications · 2021Article
- Completing the β,γ-CXY-dNTP Stereochemical Probe Toolkit: Synthetic Access to the dCTP Diastereomers andThe Journal of organic chemistry · 2020Article
- Products of Oxidative Guanine Damage Form Base Pairs with Guanine.International journal of molecular sciences · 2020Review
- Elucidation of leak-resistance DNA hybridization chain reaction with universality and extensibility.Nucleic acids research · 2020Article
- Understanding Rad51 function is a prerequisite for progress in cancer research.QRB discovery · 2020Article
- RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview.Chemical reviews · 2018Review
- Article
- Active Site Interactions Impact Phosphoryl Transfer during Replication of Damaged and Undamaged DNA by Escherichia coli DNA Polymerase I.Chemical research in toxicology · 2017Article
- Modulating the DNA polymerase β reaction equilibrium to dissect the reverse reaction.Nature chemical biology · 2017Article
- Relating DNA base-pairing in aqueous media to DNA polymerase fidelity.Nature reviews. Chemistry · 2017Article
- Conformational dynamics during high-fidelity DNA replication and translocation defined using a DNA polymerase with a fluorescent artificial amino acid.The Journal of biological chemistryArticle
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
What is the free energy source enabling high-fidelity DNA polymerases (pols) to favor incorporation of correct over incorrect base pairs by 10(3)- to 10(4)-fold, corresponding to free energy differences of ΔΔGinc∼ 5.5-7 kcal/mol? Standard ΔΔG° values (∼0.3 kcal/mol) calculated from melting temperature measurements comparing matched vs. mismatched base pairs at duplex DNA termini are far too low to explain pol accuracy. Earlier analyses suggested that pol active-site steric constraints can amplify DNA free energy differences at the transition state (kinetic selection). A recent paper [Olson et al. (2013)J Am Chem Soc135:1205-1208] used Vent pol to catalyze incorporations in the presence of inorganic pyrophosphate intended to equilibrate forward (polymerization) and backward (pyrophosphorolysis) reactions. A steady-state leveling off of incorporation profiles at long reaction times was interpreted as reaching equilibrium between polymerization and pyrophosphorolysis, yielding apparent ΔG° = -RTlnKeq, indicating ΔΔG° of 3.5-7 kcal/mol, sufficient to account for pol accuracy without need of kinetic selection. Here we perform experiments to measure and account for pyrophosphorolysis explicitly. We show that forward and reverse reactions attain steady states far from equilibrium for wrong incorporations such as G opposite T. Therefore,[Formula: see text]values obtained from such steady-state evaluations ofKeqare not dependent on DNA properties alone, but depend largely on constraints imposed on right and wrong substrates in the polymerase active site.
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