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Title: How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O -Methyltransferase

Abstract

Hybrid quantum mechanical–molecular mechanical (QM/MM) simulations are widely used in studies of enzymatic catalysis. Until recently, it has been cost prohibitive to determine the asymptotic limit of key energetic and structural properties with respect to increasingly large QM regions. Here, leveraging recent advances in electronic structure efficiency and accuracy, we investigate catalytic properties in catechol O-methyltransferase, a prototypical methyltransferase critical to human health. Using QM regions ranging in size from reactants-only (64 atoms) to nearly one-third of the entire protein (940 atoms), we show that properties such as the activation energy approach within chemical accuracy of the large-QM asymptotic limits rather slowly, requiring approximately 500–600 atoms if the QM residues are chosen simply by distance from the substrate. This slow approach to asymptotic limit is due to charge transfer from protein residues to the reacting substrates. Our large QM/MM calculations enable identification of charge separation for fragments in the transition state as a key component of enzymatic methyl transfer rate enhancement. We introduce charge shift analysis that reveals the minimum number of protein residues (approximately 11–16 residues or 200–300 atoms for COMT) needed for quantitative agreement with large-QM simulations. The identified residues are not those that would be typically selectedmore » using criteria such as chemical intuition or proximity. These results provide a recipe for a more careful determination of QM region sizes in future QM/MM studies of enzymes.« less

Authors:
 [1];  [2];  [2];  [1]
+ Show Author Affiliations
  1. SLAC National Accelerator Lab., Menlo Park, CA (United States). Photon Ultrafast Laser Science and Engineering Inst. (PULSE); Stanford Univ., CA (United States). Dept. of Chemistry
  2. Univ. of California, Berkeley, CA (United States). California Inst. for Quantitative Biosciences, Dept. of Chemistry and of Molecular and Cell Biology
Publication Date:
Research Org.:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Org.:
USDOE; USDOD
OSTI Identifier:
1360173
Grant/Contract Number:  
AC02-76SF00515; NSSEFF; GM025765; GM039296
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
Additional Journal Information:
Journal Volume: 120; Journal Issue: 44; Journal ID: ISSN 1520-6106
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Kulik, Heather J., Zhang, Jianyu, Klinman, Judith P., and Martínez, Todd J. How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O -Methyltransferase. United States: N. p., 2016. Web. doi:10.1021/acs.jpcb.6b07814.
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Kulik, Heather J., Zhang, Jianyu, Klinman, Judith P., & Martínez, Todd J. How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O -Methyltransferase. United States. https://doi.org/10.1021/acs.jpcb.6b07814
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Kulik, Heather J., Zhang, Jianyu, Klinman, Judith P., and Martínez, Todd J. Wed . "How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O -Methyltransferase". United States. https://doi.org/10.1021/acs.jpcb.6b07814. https://www.osti.gov/servlets/purl/1360173.
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@article{osti_1360173,
title = {How Large Should the QM Region Be in QM/MM Calculations? The Case of Catechol O -Methyltransferase},
author = {Kulik, Heather J. and Zhang, Jianyu and Klinman, Judith P. and Martínez, Todd J.},
abstractNote = {Hybrid quantum mechanical–molecular mechanical (QM/MM) simulations are widely used in studies of enzymatic catalysis. Until recently, it has been cost prohibitive to determine the asymptotic limit of key energetic and structural properties with respect to increasingly large QM regions. Here, leveraging recent advances in electronic structure efficiency and accuracy, we investigate catalytic properties in catechol O-methyltransferase, a prototypical methyltransferase critical to human health. Using QM regions ranging in size from reactants-only (64 atoms) to nearly one-third of the entire protein (940 atoms), we show that properties such as the activation energy approach within chemical accuracy of the large-QM asymptotic limits rather slowly, requiring approximately 500–600 atoms if the QM residues are chosen simply by distance from the substrate. This slow approach to asymptotic limit is due to charge transfer from protein residues to the reacting substrates. Our large QM/MM calculations enable identification of charge separation for fragments in the transition state as a key component of enzymatic methyl transfer rate enhancement. We introduce charge shift analysis that reveals the minimum number of protein residues (approximately 11–16 residues or 200–300 atoms for COMT) needed for quantitative agreement with large-QM simulations. The identified residues are not those that would be typically selected using criteria such as chemical intuition or proximity. These results provide a recipe for a more careful determination of QM region sizes in future QM/MM studies of enzymes.},
doi = {10.1021/acs.jpcb.6b07814},
journal = {Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry},
number = 44,
volume = 120,
place = {United States},
year = {Wed Oct 05 00:00:00 EDT 2016},
month = {Wed Oct 05 00:00:00 EDT 2016}
}
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Projected Hybrid Orbitals: A General QM/MM Method
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Quantum Chemistry on Graphical Processing Units. 2. Direct Self-Consistent-Field Implementation
journal, March 2009

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A challenge for density functionals: Self-interaction error increases for systems with a noninteger number of electrons
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H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations
journal, May 2012

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A simple clustering algorithm can be accurate enough for use in calculations of pKs in macromolecules
journal, February 2006

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The Charge Transfer Problem in Density Functional Theory Calculations of Aqueously Solvated Molecules
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Difficulties in applying pure Kohn–Sham density functional theory electronic structure methods to protein molecules
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A Convergence Study of QM/MM Isomerization Energies with the Selected Size of the QM Region for Peptidic Systems †
journal, October 2009

  • Sumowski, Chris Vanessa; Ochsenfeld, Christian
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Theoretical Modeling of Large Molecular Systems. Advances in the Local Self Consistent Field Method for Mixed Quantum Mechanics/Molecular Mechanics Calculations
journal, December 2012

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Computational Chemistry Column: Combined Quantum Mechanical and Molecular Mechanical Approaches
journal, June 1998

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