ArticleBiochemical and biophysical research communications2006
Correct and incorrect nucleotide incorporation pathways in DNA polymerase beta.
Article in Biochemical and biophysical research communications, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Understanding the Fidelity and Specificity of DNA Polymerase I.ACS omega · 2025Article
- A pre-catalytic non-covalent step governs DNA polymerase β fidelity.Nucleic acids research · 2019Article
- Molecular Mechanisms of DNA Replication and Repair Machinery: Insights from Microscopic Simulations.Advanced theory and simulations · 2019Article
- Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants.Chemical research in toxicology · 2017Article
- A Change in the Rate-Determining Step of Polymerization by the K289M DNA Polymerase β Cancer-Associated Variant.Biochemistry · 2017Article
- Uniform Free-Energy Profiles of the P-O Bond Formation and Cleavage Reactions Catalyzed by DNA Polymerases β and λ.The journal of physical chemistry. B · 2016Article
- Exploring the mechanism of DNA polymerases by analyzing the effect of mutations of active site acidic groups in Polymerase β.Proteins · 2016Article
- Insertion of oxidized nucleotide triggers rapid DNA polymerase opening.Nucleic acids research · 2016Article
- Induced Fit in the Selection of Correct versus Incorrect Nucleotides by DNA Polymerase β.Biochemistry · 2016Article
- Computational delineation of tyrosyl-substrate recognition and catalytic landscapes by the epidermal growth factor receptor tyrosine kinase domain.Molecular bioSystems · 2014Article
- Optimal and variant metal-ion routes in DNA polymerase β's conformational pathways.Journal of the American Chemical Society · 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
- Computational simulation strategies for analysis of multisubunit RNA polymerases.Chemical reviews · 2013Review
- Substrate recognition by norovirus polymerase: microsecond molecular dynamics study.Journal of computer-aided molecular design · 2013Article
- Why nature really chose phosphate.Quarterly reviews of biophysics · 2013Review
- Addressing open questions about phosphate hydrolysis pathways by careful free energy mapping.The journal of physical chemistry. B · 2013Article
- "Gate-keeper" residues and active-site rearrangements in DNA polymerase μ help discriminate non-cognate nucleotides.PLoS computational biology · 2013Article
- Perspective: pre-chemistry conformational changes in DNA polymerase mechanisms.Theoretical chemistry accounts · 2012Article
- Unfavorable electrostatic and steric interactions in DNA polymerase β E295K mutant interfere with the enzyme's pathway.Journal of the American Chemical Society · 2012Article
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2 authors.
Funding
Abstract
Tracking the structural and energetic changes in the pathways of DNA replication and repair is central to the understanding of these important processes. Here we report favorable mechanisms of the polymerase-catalyzed phosphoryl transfer reactions corresponding to correct and incorrect nucleotide incorporations in the DNA by using a novel protocol involving energy minimizations, dynamics simulations, quasi-harmonic free energy calculations, and mixed quantum mechanics/molecular mechanics dynamics simulations. Though the pathway proposed may not be unique and invites variations, geometric and energetic arguments support the series of transient intermediates in the phosphoryl transfer pathways uncovered here for both the G:C and G:A systems involving a Grotthuss hopping mechanism of proton transfer between water molecules and the three conserved aspartate residues in pol beta's active-site. In the G:C system, the rate-limiting step is the initial proton hop with a free energy of activation of at least 17 kcal/mol, which corresponds closely to measured k(pol) values. Fidelity discrimination in pol beta can be explained by a significant loss of stability of the closed ternary complex of the enzyme in the G:A system and much higher activation energy of the initial step of nucleophilic attack, namely deprotonation of terminal DNA primer O3'H group. Thus, subtle differences in the enzyme active-site between matched and mismatched base pairs generate significant differences in catalytic performance.
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