ArticleNucleic acids research2012
Preferred WMSA catalytic mechanism of the nucleotidyl transfer reaction in human DNA polymerase κ elucidates error-free bypass of a bulky DNA lesion.
Article in Nucleic acids research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- Conserved Active Site Loop Residues of E. coli DinB and Human DNA Polymerase Kappa Govern Activity.Environmental and molecular mutagenesis · 2026Article
- Comparing Force Field Treatments in QM/MM Studies of the SARS-CoV-2 RNA-Dependent RNA Polymerase (RdRp) Mechanism.Journal of chemical theory and computation · 2025Article
- Effects of the Y432S Cancer-Associated Variant on the Reaction Mechanism of Human DNA Polymerase κ.Journal of chemical information and modeling · 2024Article
- AcceleratingThe journal of physical chemistry. B · 2022Article
- Progress on Exploring the Luminescent Properties of Organic Molecular Aggregates by Multiscale Modeling.Frontiers in chemistry · 2021Review
- Two symmetric arginine residues play distinct roles inProceedings of the National Academy of Sciences of the United States of America · 2019Article
- 5-Formylcytosine mediated DNA-protein cross-links block DNA replication and induce mutations in human cells.Nucleic acids research · 2018Article
- Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants.Chemical research in toxicology · 2017Article
- Structure and mechanism of error-free replication past the major benzo[a]pyrene adduct by human DNA polymerase κ.Nucleic acids research · 2016Article
- Cooperative motion of a key positively charged residue and metal ions for DNA replication catalyzed by human DNA Polymerase-η.Nucleic acids research · 2016Article
- Born-Oppenheimer Ab Initio QM/MM Molecular Dynamics Simulations of Enzyme Reactions.Methods in enzymology · 2016Article
- A new paradigm of DNA synthesis: three-metal-ion catalysis.Cell & bioscience · 2016Review
- Structural and dynamic characterization of polymerase κ's minor groove lesion processing reveals how adduct topology impacts fidelity.Biochemistry · 2014Article
- An overview of Y-Family DNA polymerases and a case study of human DNA polymerase η.Biochemistry · 2014Review
- Variants of mouse DNA polymerase κ reveal a mechanism of efficient and accurate translesion synthesis past a benzo[a]pyrene dG adduct.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Applications of quantum mechanical/molecular mechanical methods to the chemical insertion step of DNA and RNA polymerization.Advances in protein chemistry and structural biology · 2014Review
- Molecular modeling of nucleic acid structure: energy and sampling.Current protocols in nucleic acid chemistry · 2013Review
- Article
- DNA cytosine methylation: structural and thermodynamic characterization of the epigenetic marking mechanism.Biochemistry · 2013Article
- Sirtuin Deacetylation Mechanism and Catalytic Role of the Dynamic Cofactor Binding Loop.The journal of physical chemistry letters · 2013Article
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Authors and funding
6 authors at 1 institution in 1 country.
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Abstract
Human DNA Pol κ is a polymerase enzyme, specialized for near error-free bypass of certain bulky chemical lesions to DNA that are derived from environmental carcinogens present in tobacco smoke, automobile exhaust and cooked food. By employing ab initio QM/MM-MD (Quantum Mechanics/Molecular Mechanics-Molecular Dynamics) simulations with umbrella sampling, we have determined the entire free energy profile of the nucleotidyl transfer reaction catalyzed by Pol κ and provided detailed mechanistic insights. Our results show that a variant of the Water Mediated and Substrate Assisted (WMSA) mechanism that we previously deduced for Dpo4 and T7 DNA polymerases is preferred for Pol κ as well, suggesting its broad applicability. The hydrogen on the 3'-OH primer terminus is transferred through crystal and solvent waters to the γ-phosphate of the dNTP, followed by the associative nucleotidyl transfer reaction; this is facilitated by a proton transfer from the γ-phosphate to the α,β-bridging oxygen as pyrophosphate leaves, to neutralize the evolving negative charge. MD simulations show that the near error-free incorporation of dCTP opposite the major benzo[a]pyrene-derived dG lesion is compatible with the WMSA mechanism, allowing for an essentially undisturbed pentacovalent phosphorane transition state, and explaining the bypass of this lesion with little mutation by Pol κ.
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