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Title: QM/MM MD and free energy simulations of G9α-like protein (GLP) and its mutants: Understanding the factors that determine the product specificity

Abstract

Certain lysine residues on histone tails could be methylated by protein lysine methyltransferases (PKMTs) using S-adenosyl-L-methionine (AdoMet) as the methyl donor. Since the methylation states of the target lysines play a fundamental role in the regulation of chromatin structure and gene expression, it is important to study the property of PKMTs that allows a specific number of methyl groups (one, two or three) to be added (termed as product specificity). It has been shown that the product specificity of PKMTs may be controlled in part by the existence of specific residues at the active site. One of the best examples is a Phe/Tyr switch found in many PKMTs. Here quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed on wild type G9a-like protein (GLP) and its F1209Y and Y1124F mutants for understanding the energetic origin of the product specificity and the reasons for the change of product specificity as a result of single-residue mutations at the Phe/Tyr switch as well as other positions. The free energy barriers of the methyl transfer processes calculated from our simulations are consistent with experimental data, supporting the suggestion that the relative free energy barriers may determine, at least in part,more » the product specificity of PKMTs. The changes of the free energy barriers as a result of the mutations are also discussed based on the structural information obtained from the simulations. Furthermore, the results suggest that the space and active-site interactions around the -amino group of the target lysine available for methyl addition appear to among the key structural factors in controlling the product specificity and activity of PKMTs.« less

Authors:
 [1];  [1];  [2]
+ Show Author Affiliations
  1. Univ. of Tennessee, Knoxville, TN (United States)
  2. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1265963
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 7; Journal Issue: 5; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Chu, Yuzhuo, Yao, Jianzhuang, and Guo, Hong. QM/MM MD and free energy simulations of G9α-like protein (GLP) and its mutants: Understanding the factors that determine the product specificity. United States: N. p., 2012. Web. doi:10.1371/journal.pone.0037674.
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Chu, Yuzhuo, Yao, Jianzhuang, & Guo, Hong. QM/MM MD and free energy simulations of G9α-like protein (GLP) and its mutants: Understanding the factors that determine the product specificity. United States. https://doi.org/10.1371/journal.pone.0037674
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Chu, Yuzhuo, Yao, Jianzhuang, and Guo, Hong. Fri . "QM/MM MD and free energy simulations of G9α-like protein (GLP) and its mutants: Understanding the factors that determine the product specificity". United States. https://doi.org/10.1371/journal.pone.0037674. https://www.osti.gov/servlets/purl/1265963.
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@article{osti_1265963,
title = {QM/MM MD and free energy simulations of G9α-like protein (GLP) and its mutants: Understanding the factors that determine the product specificity},
author = {Chu, Yuzhuo and Yao, Jianzhuang and Guo, Hong},
abstractNote = {Certain lysine residues on histone tails could be methylated by protein lysine methyltransferases (PKMTs) using S-adenosyl-L-methionine (AdoMet) as the methyl donor. Since the methylation states of the target lysines play a fundamental role in the regulation of chromatin structure and gene expression, it is important to study the property of PKMTs that allows a specific number of methyl groups (one, two or three) to be added (termed as product specificity). It has been shown that the product specificity of PKMTs may be controlled in part by the existence of specific residues at the active site. One of the best examples is a Phe/Tyr switch found in many PKMTs. Here quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed on wild type G9a-like protein (GLP) and its F1209Y and Y1124F mutants for understanding the energetic origin of the product specificity and the reasons for the change of product specificity as a result of single-residue mutations at the Phe/Tyr switch as well as other positions. The free energy barriers of the methyl transfer processes calculated from our simulations are consistent with experimental data, supporting the suggestion that the relative free energy barriers may determine, at least in part, the product specificity of PKMTs. The changes of the free energy barriers as a result of the mutations are also discussed based on the structural information obtained from the simulations. Furthermore, the results suggest that the space and active-site interactions around the -amino group of the target lysine available for methyl addition appear to among the key structural factors in controlling the product specificity and activity of PKMTs.},
doi = {10.1371/journal.pone.0037674},
journal = {PLoS ONE},
number = 5,
volume = 7,
place = {United States},
year = {Fri May 18 00:00:00 EDT 2012},
month = {Fri May 18 00:00:00 EDT 2012}
}
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Works referenced in this record:

Structural Biology of Human H3K9 Methyltransferases
journal, January 2010

Energy Triplets for Writing Epigenetic Marks: Insights from QM/MM Free-Energy Simulations of Protein Lysine Methyltransferases
journal, November 2009

  • Xu, Qin; Chu, Yu-zhuo; Guo, Hao-Bo
  • Chemistry - A European Journal, Vol. 15, Issue 46
  • DOI: 10.1002/chem.200902297

Primers on chromatin
journal, November 2007

Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity
journal, May 2007

  • Guo, H. -B.; Guo, H.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 21
  • DOI: 10.1073/pnas.0702981104

Active site dynamics in protein molecules: A stochastic boundary molecular-dynamics approach
journal, May 1985

Communication: Conformation state diagram of polypeptides: A chain length induced α-β transition
journal, August 2011

  • Ricchiuto, Piero; Brukhno, Andrey V.; Paci, Emanuele
  • The Journal of Chemical Physics, Vol. 135, Issue 6
  • DOI: 10.1063/1.3624928

A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations
journal, July 1990

  • Field, Martin J.; Bash, Paul A.; Karplus, Martin
  • Journal of Computational Chemistry, Vol. 11, Issue 6
  • DOI: 10.1002/jcc.540110605

Specificity and mechanism of the histone methyltransferase Pr-Set7
journal, June 2005

How Do SET-Domain Protein Lysine Methyltransferases Achieve the Methylation State Specificity? Revisited by Ab Initio QM/MM Molecular Dynamics Simulations
journal, March 2008

  • Hu, Po; Wang, Shenglong; Zhang, Yingkai
  • Journal of the American Chemical Society, Vol. 130, Issue 12
  • DOI: 10.1021/ja075896n

Reading signals on the nucleosome with a new nomenclature for modified histones
journal, February 2005

  • Turner, Bryan M.
  • Nature Structural & Molecular Biology, Vol. 12, Issue 2
  • DOI: 10.1038/nsmb0205-110

How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
journal, November 2007

  • Taverna, Sean D.; Li, Haitao; Ruthenburg, Alexander J.
  • Nature Structural & Molecular Biology, Vol. 14, Issue 11
  • DOI: 10.1038/nsmb1338

CHARMM: A program for macromolecular energy, minimization, and dynamics calculations
journal, July 1983

  • Brooks, Bernard R.; Bruccoleri, Robert E.; Olafson, Barry D.
  • Journal of Computational Chemistry, Vol. 4, Issue 2
  • DOI: 10.1002/jcc.540040211

THE weighted histogram analysis method for free-energy calculations on biomolecules. I. The method
journal, October 1992

  • Kumar, Shankar; Rosenberg, John M.; Bouzida, Djamal
  • Journal of Computational Chemistry, Vol. 13, Issue 8
  • DOI: 10.1002/jcc.540130812

Structural origins for the product specificity of SET domain protein methyltransferases
journal, December 2008

  • Couture, J. -F.; Dirk, L. M. A.; Brunzelle, J. S.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 52
  • DOI: 10.1073/pnas.0806712105

Ab Initio Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulation of Enzyme Catalysis:  The Case of Histone Lysine Methyltransferase SET7/9
journal, April 2007

  • Wang, Shenglong; Hu, Po; Zhang, Yingkai
  • The Journal of Physical Chemistry B, Vol. 111, Issue 14
  • DOI: 10.1021/jp067147i

Structure and catalytic mechanism of the human histone methyltransferase SET7/9
journal, January 2003

  • Xiao, Bing; Jing, Chun; Wilson, Jonathan R.
  • Nature, Vol. 421, Issue 6923
  • DOI: 10.1038/nature01378

Simulation of activation free energies in molecular systems
journal, August 1996

  • Neria, Eyal; Fischer, Stefan; Karplus, Martin
  • The Journal of Chemical Physics, Vol. 105, Issue 5
  • DOI: 10.1063/1.472061

Comparison of simple potential functions for simulating liquid water
journal, July 1983

  • Jorgensen, William L.; Chandrasekhar, Jayaraman; Madura, Jeffry D.
  • The Journal of Chemical Physics, Vol. 79, Issue 2
  • DOI: 10.1063/1.445869

The diverse functions of histone lysine methylation
journal, November 2005

  • Martin, Cyrus; Zhang, Yi
  • Nature Reviews Molecular Cell Biology, Vol. 6, Issue 11
  • DOI: 10.1038/nrm1761

Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases
journal, April 2008

  • Zhang, X.; Bruice, T. C.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 15
  • DOI: 10.1073/pnas.0801788105

Monte Carlo free energy estimates using non-Boltzmann sampling: Application to the sub-critical Lennard-Jones fluid
journal, October 1974

All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins †
journal, April 1998

  • MacKerell, A. D.; Bashford, D.; Bellott, M.
  • The Journal of Physical Chemistry B, Vol. 102, Issue 18
  • DOI: 10.1021/jp973084f

Structure of the Neurospora SET Domain Protein DIM-5, a Histone H3 Lysine Methyltransferase
journal, October 2002

Modeling a New Water Channel That Allows SET9 to Dimethylate p53
journal, May 2011

Boxed Molecular Dynamics: A Simple and General Technique for Accelerating Rare Event Kinetics and Mapping Free Energy in Large Molecular Systems
journal, December 2009

  • Glowacki, David R.; Paci, Emanuele; Shalashilin, Dmitrii V.
  • The Journal of Physical Chemistry B, Vol. 113, Issue 52
  • DOI: 10.1021/jp9074898

The language of covalent histone modifications
journal, January 2000

  • Strahl, Brian D.; Allis, C. David
  • Nature, Vol. 403, Issue 6765
  • DOI: 10.1038/47412

A QM/MM Implementation of the Self-Consistent Charge Density Functional Tight Binding (SCC-DFTB) Method
journal, January 2001

  • Cui, Qiang; Elstner, Marcus; Kaxiras, Efthimios
  • The Journal of Physical Chemistry B, Vol. 105, Issue 2
  • DOI: 10.1021/jp0029109

Structural Basis for the Product Specificity of Histone Lysine Methyltransferases
journal, July 2003

Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase
journal, June 2005

Specificity and Mechanism of the Histone Methyltransferase Pr-Set7
dataset, January 2005

  • Xiao, Bing; Jing, Chun; Kelly, Geoff
  • Biological Magnetic Resonance Bank
  • DOI: 10.13018/bmr6628

Active site dynamics in protein molecules: A stochastic boundary molecular-dynamics approach
journal, May 1985

Energy Triplets for Writing Epigenetic Marks: Insights from QM/MM Free-Energy Simulations of Protein Lysine Methyltransferases
journal, November 2009

  • Xu, Qin; Chu, Yu-zhuo; Guo, Hao-Bo
  • Chemistry - A European Journal, Vol. 15, Issue 46
  • DOI: 10.1002/chem.200902297

A combined quantum mechanical and molecular mechanical potential for molecular dynamics simulations
journal, July 1990

  • Field, Martin J.; Bash, Paul A.; Karplus, Martin
  • Journal of Computational Chemistry, Vol. 11, Issue 6
  • DOI: 10.1002/jcc.540110605

Structure of SET domain proteins: a new twist on histone methylation
journal, February 2003

Cracking the Histone Code One, Two, Three Methyls, You're Out!
journal, July 2003

Boxed Molecular Dynamics: A Simple and General Technique for Accelerating Rare Event Kinetics and Mapping Free Energy in Large Molecular Systems
journal, December 2009

  • Glowacki, David R.; Paci, Emanuele; Shalashilin, Dmitrii V.
  • The Journal of Physical Chemistry B, Vol. 113, Issue 52
  • DOI: 10.1021/jp9074898

All-Atom Empirical Potential for Molecular Modeling and Dynamics Studies of Proteins †
journal, April 1998

  • MacKerell, A. D.; Bashford, D.; Bellott, M.
  • The Journal of Physical Chemistry B, Vol. 102, Issue 18
  • DOI: 10.1021/jp973084f

Structure and catalytic mechanism of the human histone methyltransferase SET7/9
journal, January 2003

  • Xiao, Bing; Jing, Chun; Wilson, Jonathan R.
  • Nature, Vol. 421, Issue 6923
  • DOI: 10.1038/nature01378

The diverse functions of histone lysine methylation
journal, November 2005

  • Martin, Cyrus; Zhang, Yi
  • Nature Reviews Molecular Cell Biology, Vol. 6, Issue 11
  • DOI: 10.1038/nrm1761

How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
journal, November 2007

  • Taverna, Sean D.; Li, Haitao; Ruthenburg, Alexander J.
  • Nature Structural & Molecular Biology, Vol. 14, Issue 11
  • DOI: 10.1038/nsmb1338

Communication: Conformation state diagram of polypeptides: A chain length induced α-β transition
journal, August 2011

  • Ricchiuto, Piero; Brukhno, Andrey V.; Paci, Emanuele
  • The Journal of Chemical Physics, Vol. 135, Issue 6
  • DOI: 10.1063/1.3624928

Simulation of activation free energies in molecular systems
journal, August 1996

  • Neria, Eyal; Fischer, Stefan; Karplus, Martin
  • The Journal of Chemical Physics, Vol. 105, Issue 5
  • DOI: 10.1063/1.472061

Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity
journal, May 2007

  • Guo, H. -B.; Guo, H.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 21
  • DOI: 10.1073/pnas.0702981104

Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases
journal, April 2008

  • Zhang, X.; Bruice, T. C.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 15
  • DOI: 10.1073/pnas.0801788105

Structural origins for the product specificity of SET domain protein methyltransferases
journal, December 2008

  • Couture, J. -F.; Dirk, L. M. A.; Brunzelle, J. S.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 52
  • DOI: 10.1073/pnas.0806712105

SET7/9 Catalytic Mutants Reveal the Role of Active Site Water Molecules in Lysine Multiple Methylation
journal, August 2010

  • Del Rizzo, Paul A.; Couture, Jean-François; Dirk, Lynnette M. A.
  • Journal of Biological Chemistry, Vol. 285, Issue 41
  • DOI: 10.1074/jbc.m110.114587

In Vitro and in Vivo Analyses of a Phe/Tyr Switch Controlling Product Specificity of Histone Lysine Methyltransferases
journal, December 2004

  • Collins, Robert E.; Tachibana, Makoto; Tamaru, Hisashi
  • Journal of Biological Chemistry, Vol. 280, Issue 7
  • DOI: 10.1074/jbc.m410483200

Specificity and mechanism of the histone methyltransferase Pr-Set7
journal, June 2005

Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase
journal, June 2005

Structural Biology of Human H3K9 Methyltransferases
journal, January 2010

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    Lysine Possesses the Optimal Chain Length for Histone Lysine Methyltransferase Catalysis
    journal, November 2017

    • Temimi, Abbas H. K. Al; Reddy, Y. Vijayendar; White, Paul B.
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    The nucleophilic amino group of lysine is central for histone lysine methyltransferase catalysis
    journal, September 2019

    • Al Temimi, Abbas H. K.; Amatdjais-Groenen, Helene I. V.; Reddy, Y. Vijayendar
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    • DOI: 10.1038/s42004-019-0210-8

    Catalytic promiscuity of the non-native FPP substrate in the TEAS enzyme: non-negligible flexibility of the carbocation intermediate
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    • Physical Chemistry Chemical Physics, Vol. 20, Issue 22
    • DOI: 10.1039/c8cp02262c

    Lysine Ethylation by Histone Lysine Methyltransferases
    text, January 2020

    Lysine Ethylation by Histone Lysine Methyltransferases
    journal, October 2019

    • Al Temimi, Abbas H. K.; Martin, Michael; Meng, Qingxi
    • ChemBioChem, Vol. 21, Issue 3
    • DOI: 10.1002/cbic.201900359

    Lysine Possesses the Optimal Chain Length for Histone Lysine Methyltransferase Catalysis
    journal, November 2017

    • Temimi, Abbas H. K. Al; Reddy, Y. Vijayendar; White, Paul B.
    • Scientific Reports, Vol. 7, Issue 1
    • DOI: 10.1038/s41598-017-16128-4

    Predicting the Functions and Specificity of Triterpenoid Synthases: A Mechanism-Based Multi-intermediate Docking Approach
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