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Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis

DNA methyltransferases play crucial roles in establishing and maintenance of DNA methylation, which is an important epigenetic mark. Flipping the target cytosine out of the DNA helical stack and into the active site of protein provides DNA methyltransferases with an opportunity to access and modify...

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Autores principales: Jin, Lu, Ye, Fei, Zhao, Dan, Chen, Shijie, Zhu, Kongkai, Zheng, Mingyue, Jiang, Ren-Wang, Jiang, Hualiang, Luo, Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi Publishing Corporation 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090504/
https://www.ncbi.nlm.nih.gov/pubmed/25045662
http://dx.doi.org/10.1155/2014/304563
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author Jin, Lu
Ye, Fei
Zhao, Dan
Chen, Shijie
Zhu, Kongkai
Zheng, Mingyue
Jiang, Ren-Wang
Jiang, Hualiang
Luo, Cheng
author_facet Jin, Lu
Ye, Fei
Zhao, Dan
Chen, Shijie
Zhu, Kongkai
Zheng, Mingyue
Jiang, Ren-Wang
Jiang, Hualiang
Luo, Cheng
author_sort Jin, Lu
collection PubMed
description DNA methyltransferases play crucial roles in establishing and maintenance of DNA methylation, which is an important epigenetic mark. Flipping the target cytosine out of the DNA helical stack and into the active site of protein provides DNA methyltransferases with an opportunity to access and modify the genetic information hidden in DNA. To investigate the conversion process of base flipping in the HhaI methyltransferase (M.HhaI), we performed different molecular simulation approaches on M.HhaI-DNA-S-adenosylhomocysteine ternary complex. The results demonstrate that the nonspecific binding of DNA to M.HhaI is initially induced by electrostatic interactions. Differences in chemical environment between the major and minor grooves determine the orientation of DNA. Gln237 at the target recognition loop recognizes the GCGC base pair from the major groove side by hydrogen bonds. In addition, catalytic loop motion is a key factor during this process. Our study indicates that base flipping is likely to be an “induced-fit” process. This study provides a solid foundation for future studies on the discovery and development of mechanism-based DNA methyltransferases regulators.
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spelling pubmed-40905042014-07-20 Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis Jin, Lu Ye, Fei Zhao, Dan Chen, Shijie Zhu, Kongkai Zheng, Mingyue Jiang, Ren-Wang Jiang, Hualiang Luo, Cheng Biomed Res Int Research Article DNA methyltransferases play crucial roles in establishing and maintenance of DNA methylation, which is an important epigenetic mark. Flipping the target cytosine out of the DNA helical stack and into the active site of protein provides DNA methyltransferases with an opportunity to access and modify the genetic information hidden in DNA. To investigate the conversion process of base flipping in the HhaI methyltransferase (M.HhaI), we performed different molecular simulation approaches on M.HhaI-DNA-S-adenosylhomocysteine ternary complex. The results demonstrate that the nonspecific binding of DNA to M.HhaI is initially induced by electrostatic interactions. Differences in chemical environment between the major and minor grooves determine the orientation of DNA. Gln237 at the target recognition loop recognizes the GCGC base pair from the major groove side by hydrogen bonds. In addition, catalytic loop motion is a key factor during this process. Our study indicates that base flipping is likely to be an “induced-fit” process. This study provides a solid foundation for future studies on the discovery and development of mechanism-based DNA methyltransferases regulators. Hindawi Publishing Corporation 2014 2014-06-19 /pmc/articles/PMC4090504/ /pubmed/25045662 http://dx.doi.org/10.1155/2014/304563 Text en Copyright © 2014 Lu Jin et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Jin, Lu
Ye, Fei
Zhao, Dan
Chen, Shijie
Zhu, Kongkai
Zheng, Mingyue
Jiang, Ren-Wang
Jiang, Hualiang
Luo, Cheng
Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis
title Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis
title_full Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis
title_fullStr Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis
title_full_unstemmed Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis
title_short Metadynamics Simulation Study on the Conformational Transformation of HhaI Methyltransferase: An Induced-Fit Base-Flipping Hypothesis
title_sort metadynamics simulation study on the conformational transformation of hhai methyltransferase: an induced-fit base-flipping hypothesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090504/
https://www.ncbi.nlm.nih.gov/pubmed/25045662
http://dx.doi.org/10.1155/2014/304563
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