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Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase.

Publication ,  Journal Article
Mondal, M; Yang, Y; Yang, L; Yang, W; Gao, YQ
Published in: Journal of chemical theory and computation
December 2018

Methylation of cytosine is the common epigenetic modification in genomes ranging from bacteria to mammals, and aberrant methylation leads to human diseases including cancer. Recognition of a cognate DNA sequence by DNA methyltransferases and flipping of a target base into the enzyme active site pocket are the key steps in DNA methylation. Using molecular dynamics simulations and enhanced sampling techniques here we elucidate the role of conformational fluctuations of protein and active or passive involvement of protein elements that mediate base flipping and formation of the closed catalytic complex. The free energy profiles for the flipping of target cytosine into the enzyme active site support the major groove base eversion pathway; and the results show that the closed state of enzyme increases the free energy barrier, whereas the open state reduces it. We found that the interactions of the key loop residues of protein with cognate DNA altered the protein motions, and modulation of protein fluctuations relates to the closed catalytic complex formation. Methylation of cytosine in the active site of the closed complex destabilizes the interactions of catalytic loop residues with cognate DNA and reduces the stability of the closed state. Our study provides microscopic insights on the base flipping mechanism coupled with enzyme's loop motions and provides evidence for the role of conformational fluctuations of protein in the enzyme-catalyzed DNA processing mechanism.

Duke Scholars

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Published In

Journal of chemical theory and computation

DOI

EISSN

1549-9626

ISSN

1549-9618

Publication Date

December 2018

Volume

14

Issue

12

Start / End Page

6679 / 6689

Related Subject Headings

  • Protein Conformation
  • Nucleic Acid Conformation
  • Molecular Dynamics Simulation
  • Entropy
  • DNA-Cytosine Methylases
  • DNA Methylation
  • DNA
  • Chemical Physics
  • Base Sequence
  • 3407 Theoretical and computational chemistry
 

Citation

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Mondal, M., Yang, Y., Yang, L., Yang, W., & Gao, Y. Q. (2018). Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase. Journal of Chemical Theory and Computation, 14(12), 6679–6689. https://doi.org/10.1021/acs.jctc.8b00732
Mondal, Manas, Ying Yang, Lijiang Yang, Weitao Yang, and Yi Qin Gao. “Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase.Journal of Chemical Theory and Computation 14, no. 12 (December 2018): 6679–89. https://doi.org/10.1021/acs.jctc.8b00732.
Mondal M, Yang Y, Yang L, Yang W, Gao YQ. Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase. Journal of chemical theory and computation. 2018 Dec;14(12):6679–89.
Mondal, Manas, et al. “Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase.Journal of Chemical Theory and Computation, vol. 14, no. 12, Dec. 2018, pp. 6679–89. Epmc, doi:10.1021/acs.jctc.8b00732.
Mondal M, Yang Y, Yang L, Yang W, Gao YQ. Role of Conformational Fluctuations of Protein toward Methylation in DNA by Cytosine-5-methyltransferase. Journal of chemical theory and computation. 2018 Dec;14(12):6679–6689.
Journal cover image

Published In

Journal of chemical theory and computation

DOI

EISSN

1549-9626

ISSN

1549-9618

Publication Date

December 2018

Volume

14

Issue

12

Start / End Page

6679 / 6689

Related Subject Headings

  • Protein Conformation
  • Nucleic Acid Conformation
  • Molecular Dynamics Simulation
  • Entropy
  • DNA-Cytosine Methylases
  • DNA Methylation
  • DNA
  • Chemical Physics
  • Base Sequence
  • 3407 Theoretical and computational chemistry