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Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.

Publication ,  Journal Article
Li, P; Rangadurai, A; Al-Hashimi, HM; Hammes-Schiffer, S
Published in: J Am Chem Soc
June 24, 2020

DNA bases can adopt energetically unfavorable tautomeric forms that enable the formation of Watson-Crick-like (WC-like) mispairs, which have been proposed to give rise to spontaneous mutations in DNA and misincorporation errors in DNA replication and translation. Previous NMR and computational studies have indicated that the population of WC-like guanine-thymine (G-T) mispairs depends on the environment, such as the local nucleic acid sequence and solvation. To investigate these environmental effects, herein G-T mispair tautomerization processes are studied computationally in aqueous solution, in A-form and B-form DNA duplexes, and within the active site of a DNA polymerase λ variant. The wobble G-T (wG-T), WC-like G-T*, and WC-like G*-T forms are considered, where * indicates the enol tautomer of the base. The minimum free energy paths for the tautomerization from the wG-T to the WC-like G-T* and from the WC-like G-T* to the WC-like G*-T are computed with mixed quantum mechanical/molecular mechanical (QM/MM) free energy simulations. The reaction free energies and free energy barriers are found to be significantly influenced by the environment. The wG-T→G-T* tautomerization is predicted to be endoergic in aqueous solution and the DNA duplexes but slightly exoergic in the polymerase, with Arg517 and Asn513 providing electrostatic stabilization of G-T*. The G-T*→G*-T tautomerization is also predicted to be slightly more thermodynamically favorable in the polymerase relative to these DNA duplexes. These simulations are consistent with an experimentally driven kinetic misincorporation model suggesting that G-T mispair tautomerization occurs in the ajar polymerase conformation or concertedly with the transition from the ajar to the closed polymerase conformation. Furthermore, the order of the associated two proton transfer reactions is predicted to be different in the polymerase than in aqueous solution and the DNA duplexes. These studies highlight the impact of the environment on the thermodynamics, kinetics, and fundamental mechanisms of G-T mispair tautomerization, which plays a role in a wide range of biochemically important processes.

Duke Scholars

Published In

J Am Chem Soc

DOI

EISSN

1520-5126

Publication Date

June 24, 2020

Volume

142

Issue

25

Start / End Page

11183 / 11191

Location

United States

Related Subject Headings

  • Thymine
  • Thermodynamics
  • Quantum Theory
  • Models, Molecular
  • Isomerism
  • Guanine
  • General Chemistry
  • DNA, B-Form
  • DNA, A-Form
  • DNA Polymerase beta
 

Citation

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Li, P., Rangadurai, A., Al-Hashimi, H. M., & Hammes-Schiffer, S. (2020). Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations. J Am Chem Soc, 142(25), 11183–11191. https://doi.org/10.1021/jacs.0c03774
Li, Pengfei, Atul Rangadurai, Hashim M. Al-Hashimi, and Sharon Hammes-Schiffer. “Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.J Am Chem Soc 142, no. 25 (June 24, 2020): 11183–91. https://doi.org/10.1021/jacs.0c03774.
Li P, Rangadurai A, Al-Hashimi HM, Hammes-Schiffer S. Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations. J Am Chem Soc. 2020 Jun 24;142(25):11183–91.
Li, Pengfei, et al. “Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.J Am Chem Soc, vol. 142, no. 25, June 2020, pp. 11183–91. Pubmed, doi:10.1021/jacs.0c03774.
Li P, Rangadurai A, Al-Hashimi HM, Hammes-Schiffer S. Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations. J Am Chem Soc. 2020 Jun 24;142(25):11183–11191.
Journal cover image

Published In

J Am Chem Soc

DOI

EISSN

1520-5126

Publication Date

June 24, 2020

Volume

142

Issue

25

Start / End Page

11183 / 11191

Location

United States

Related Subject Headings

  • Thymine
  • Thermodynamics
  • Quantum Theory
  • Models, Molecular
  • Isomerism
  • Guanine
  • General Chemistry
  • DNA, B-Form
  • DNA, A-Form
  • DNA Polymerase beta