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 »
- Authors:
-
- 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
- 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.
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
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.
@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}
}
Web of Science
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