Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations
Abstract
Protein arginine methyltransferases (PRMTs) catalyze the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet) to arginine residues. There are three types of PRMTs (I, II and III) that produce different methylation products, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and monomethylarginine (MMA). Since these different methylations can lead to different biological consequences, understanding the origin of product specificity of PRMTs is of considerable interest. In this article, the quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed to study SDMA catalyzed by the Type II PRMT5 on the basis of experimental observation that the dimethylated product is generated through a distributive fashion. The simulations have identified some important interactions and proton transfers during the catalysis. Similar to the cases involving Type I PRMTs, a conserved Glu residue (Glu435) in PRMT5 is suggested to function as general base catalyst based on the result of the simulations. Moreover, our results show that PRMT5 has an energetic preference for the first methylation on N-1 followed by the second methylation on a different -guanidino nitrogen of arginine (N-2).The first and second methyl transfers are estimated to have free energy barriers of 19-20 and 18-19 kcal/mol respectively. The computer simulations suggestmore »
- Authors:
-
- Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Dalian Univ. of Technology (China)
- Univ. of Tennessee, Knoxville, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1336584
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecules
- Additional Journal Information:
- Journal Volume: 20; Journal Issue: 6; Journal ID: ISSN 1420-3049
- Publisher:
- MDPI
- Country of Publication:
- United States
- Language:
- English
- Subject:
- protein arginine methyltransferase (PRMT); symmetric dimethylarginine (SDMA); asymmetric dimethylarginine (ADMA); PRODUCT SPECIFICITY; CRYSTAL-STRUCTURE; DYNAMICS; DIMETHYLATION; ARABIDOPSIS; MECHANISM; COMPLEX; BINDING; INSIGHTS; RECEPTOR
Citation Formats
Yue, Yufei, CHu, Yuzhuo, and Guo, Hong. Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations. United States: N. p., 2015.
Web. doi:10.3390/molecules200610032.
Yue, Yufei, CHu, Yuzhuo, & Guo, Hong. Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations. United States. https://doi.org/10.3390/molecules200610032
Yue, Yufei, CHu, Yuzhuo, and Guo, Hong. Thu .
"Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations". United States. https://doi.org/10.3390/molecules200610032. https://www.osti.gov/servlets/purl/1336584.
@article{osti_1336584,
title = {Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations},
author = {Yue, Yufei and CHu, Yuzhuo and Guo, Hong},
abstractNote = {Protein arginine methyltransferases (PRMTs) catalyze the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet) to arginine residues. There are three types of PRMTs (I, II and III) that produce different methylation products, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and monomethylarginine (MMA). Since these different methylations can lead to different biological consequences, understanding the origin of product specificity of PRMTs is of considerable interest. In this article, the quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed to study SDMA catalyzed by the Type II PRMT5 on the basis of experimental observation that the dimethylated product is generated through a distributive fashion. The simulations have identified some important interactions and proton transfers during the catalysis. Similar to the cases involving Type I PRMTs, a conserved Glu residue (Glu435) in PRMT5 is suggested to function as general base catalyst based on the result of the simulations. Moreover, our results show that PRMT5 has an energetic preference for the first methylation on N-1 followed by the second methylation on a different -guanidino nitrogen of arginine (N-2).The first and second methyl transfers are estimated to have free energy barriers of 19-20 and 18-19 kcal/mol respectively. The computer simulations suggest a distinctive catalytic mechanism of symmetric dimethylation that seems to be different from asymmetric dimethylation.},
doi = {10.3390/molecules200610032},
journal = {Molecules},
number = 6,
volume = 20,
place = {United States},
year = {Thu Jan 01 00:00:00 EST 2015},
month = {Thu Jan 01 00:00:00 EST 2015}
}
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Arginine methylation mediated by the Arabidopsis homolog of PRMT5 is essential for proper pre-mRNA splicing
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Type II protein arginine methyltransferase 5 (PRMT5) is required for circadian period determination in Arabidopsis thaliana
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Crystal structure of the human PRMT5:MEP50 complex
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Caenorhabditis elegans Protein Arginine Methyltransferase PRMT-5 Negatively Regulates DNA Damage-Induced Apoptosis
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QM/MM MD and Free Energy Simulations of G9a-Like Protein (GLP) and Its Mutants: Understanding the Factors that Determine the Product Specificity
journal, May 2012
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Crystal Structure of Arginine Methyltransferase 6 from Trypanosoma brucei
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Histone arginine methylation and its dynamic regulation
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Works referencing / citing this record:
The nucleophilic amino group of lysine is central for histone lysine methyltransferase catalysis
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