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

Journal Article · · Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry
 [1];  [2];  [2];  [1]
  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
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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.

Research Organization:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Organization:
USDOE; USDOD
Grant/Contract Number:
AC02-76SF00515; NSSEFF; GM025765; GM039296
OSTI ID:
1360173
Journal Information:
Journal of Physical Chemistry. B, Condensed Matter, Materials, Surfaces, Interfaces and Biophysical Chemistry, Vol. 120, Issue 44; ISSN 1520-6106
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 130 works
Citation information provided by
Web of Science

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NAMD goes quantum: an integrative suite for hybrid simulations journal March 2018
New Insights into the Catalytic Mechanism of Aldose Reductase: A QM/MM Study journal September 2017
How accurate are approximate quantum chemical methods at modelling solute–solvent interactions in solvated clusters? journal January 2020
Reactive molecular dynamics: From small molecules to proteins text January 2018
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