Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: The case of histone lysine methyltransferase SET7/9

Shenglong Wang, Po Hu, Yingkai Zhang

Research output: Contribution to journalArticle

Abstract

To elucidate enzyme catalysis through computer simulation, a prerequisite is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio quantum mechanical/molecular mechanical approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9 and its corresponding uncatalyzed reaction in aqueous solution, respectively. Our calculated activation free energy barrier for the enzyme catalyzed reaction is 22.5 kcal/mol, which agrees very well with the experimental value of 20.9 kcal/mol. The difference in potential of mean force between a corresponding prereaction state and the transition state for the solution reaction is computed to be 30.9 kcal/mol. Thus, our simulations indicate that the enzyme SET7/9 plays an essential catalytic role in significantly lowering the barrier for the methyl-transfer reaction step. For the reaction in solution, it is found that the hydrogen bond network near the reaction center undergoes a significant change, and there is a strong shift in electrostatic field from the prereaction state to the transition state, whereas for the enzyme reaction, such an effect is much smaller and the enzyme SET7/9 is found to provide a preorganized electrostatic environment to facilitate the methyl-transfer reaction. Meanwhile, we find that the transition state in the enzyme reaction is a little more dissociative than that in solution.

Original languageEnglish (US)
Pages (from-to)3758-3764
Number of pages7
JournalJournal of Physical Chemistry B
Volume111
Issue number14
DOIs
StatePublished - Apr 12 2007

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Histone-Lysine N-Methyltransferase
lysine
Catalysis
catalysis
Molecular dynamics
enzymes
Enzymes
molecular dynamics
Computer simulation
Free energy
simulation
Energy barriers
free energy
Electrostatics
Hydrogen bonds
Chemical activation
Electric fields
Sampling

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

Cite this

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title = "Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: The case of histone lysine methyltransferase SET7/9",
abstract = "To elucidate enzyme catalysis through computer simulation, a prerequisite is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio quantum mechanical/molecular mechanical approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9 and its corresponding uncatalyzed reaction in aqueous solution, respectively. Our calculated activation free energy barrier for the enzyme catalyzed reaction is 22.5 kcal/mol, which agrees very well with the experimental value of 20.9 kcal/mol. The difference in potential of mean force between a corresponding prereaction state and the transition state for the solution reaction is computed to be 30.9 kcal/mol. Thus, our simulations indicate that the enzyme SET7/9 plays an essential catalytic role in significantly lowering the barrier for the methyl-transfer reaction step. For the reaction in solution, it is found that the hydrogen bond network near the reaction center undergoes a significant change, and there is a strong shift in electrostatic field from the prereaction state to the transition state, whereas for the enzyme reaction, such an effect is much smaller and the enzyme SET7/9 is found to provide a preorganized electrostatic environment to facilitate the methyl-transfer reaction. Meanwhile, we find that the transition state in the enzyme reaction is a little more dissociative than that in solution.",
author = "Shenglong Wang and Po Hu and Yingkai Zhang",
year = "2007",
month = "4",
day = "12",
doi = "10.1021/jp067147i",
language = "English (US)",
volume = "111",
pages = "3758--3764",
journal = "Journal of Physical Chemistry B Materials",
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T2 - The case of histone lysine methyltransferase SET7/9

AU - Wang, Shenglong

AU - Hu, Po

AU - Zhang, Yingkai

PY - 2007/4/12

Y1 - 2007/4/12

N2 - To elucidate enzyme catalysis through computer simulation, a prerequisite is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio quantum mechanical/molecular mechanical approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9 and its corresponding uncatalyzed reaction in aqueous solution, respectively. Our calculated activation free energy barrier for the enzyme catalyzed reaction is 22.5 kcal/mol, which agrees very well with the experimental value of 20.9 kcal/mol. The difference in potential of mean force between a corresponding prereaction state and the transition state for the solution reaction is computed to be 30.9 kcal/mol. Thus, our simulations indicate that the enzyme SET7/9 plays an essential catalytic role in significantly lowering the barrier for the methyl-transfer reaction step. For the reaction in solution, it is found that the hydrogen bond network near the reaction center undergoes a significant change, and there is a strong shift in electrostatic field from the prereaction state to the transition state, whereas for the enzyme reaction, such an effect is much smaller and the enzyme SET7/9 is found to provide a preorganized electrostatic environment to facilitate the methyl-transfer reaction. Meanwhile, we find that the transition state in the enzyme reaction is a little more dissociative than that in solution.

AB - To elucidate enzyme catalysis through computer simulation, a prerequisite is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio quantum mechanical/molecular mechanical approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9 and its corresponding uncatalyzed reaction in aqueous solution, respectively. Our calculated activation free energy barrier for the enzyme catalyzed reaction is 22.5 kcal/mol, which agrees very well with the experimental value of 20.9 kcal/mol. The difference in potential of mean force between a corresponding prereaction state and the transition state for the solution reaction is computed to be 30.9 kcal/mol. Thus, our simulations indicate that the enzyme SET7/9 plays an essential catalytic role in significantly lowering the barrier for the methyl-transfer reaction step. For the reaction in solution, it is found that the hydrogen bond network near the reaction center undergoes a significant change, and there is a strong shift in electrostatic field from the prereaction state to the transition state, whereas for the enzyme reaction, such an effect is much smaller and the enzyme SET7/9 is found to provide a preorganized electrostatic environment to facilitate the methyl-transfer reaction. Meanwhile, we find that the transition state in the enzyme reaction is a little more dissociative than that in solution.

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