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Comparison of QM/MM Methods To Obtain Ligand-Binding Free Energies

Olsson, Martin A. LU and Ryde, Ulf LU orcid (2017) In Journal of Chemical Theory and Computation 13(5). p.2245-2253
Abstract

We have compared two approaches to calculate relative binding free energies employing molecular dynamics simulations at the combined quantum-mechanical/molecular mechanics (QM/MM) level. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavitand host system. The ligand is treated with the semiempirical PM6-DH+ QM method. In the first approach, we perform direct alchemical QM/MM free energy perturbation (FEP). In the second, reference-potential approach, we convert the ligands with FEP at the molecular mechanics (MM) level and then perform also MM → QM/MM FEP for each ligand. We show that the two approaches give identical results within statistical uncertainty. For the reference-potential... (More)

We have compared two approaches to calculate relative binding free energies employing molecular dynamics simulations at the combined quantum-mechanical/molecular mechanics (QM/MM) level. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavitand host system. The ligand is treated with the semiempirical PM6-DH+ QM method. In the first approach, we perform direct alchemical QM/MM free energy perturbation (FEP). In the second, reference-potential approach, we convert the ligands with FEP at the molecular mechanics (MM) level and then perform also MM → QM/MM FEP for each ligand. We show that the two approaches give identical results within statistical uncertainty. For the reference-potential approach, the MM → QM/MM perturbation converges in terms of energies, uncertainties, and overlap measures with two intermediate states, giving a precision of 0.5-0.9 kJ/mol for all eight transformations considered. On the other hand, the QM/MM-FEP approach requires 17-18 intermediate states, showing that the reference-potential approach is more effective. Previous calculations with single-step exponential averaging (i.e., entirely avoiding QM/MM simulations) required fewer QM/MM energy calculations, but they gave worse precision and involved approximations with an unclear effect on the results.

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type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
13
issue
5
pages
9 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:28355487
  • wos:000401221300033
  • scopus:85019167149
ISSN
1549-9618
DOI
10.1021/acs.jctc.6b01217
language
English
LU publication?
yes
id
e9f3126b-f7bf-4a77-81a0-fc96219784b4
date added to LUP
2017-05-31 08:33:27
date last changed
2025-01-07 14:27:11
@article{e9f3126b-f7bf-4a77-81a0-fc96219784b4,
  abstract     = {{<p>We have compared two approaches to calculate relative binding free energies employing molecular dynamics simulations at the combined quantum-mechanical/molecular mechanics (QM/MM) level. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavitand host system. The ligand is treated with the semiempirical PM6-DH+ QM method. In the first approach, we perform direct alchemical QM/MM free energy perturbation (FEP). In the second, reference-potential approach, we convert the ligands with FEP at the molecular mechanics (MM) level and then perform also MM → QM/MM FEP for each ligand. We show that the two approaches give identical results within statistical uncertainty. For the reference-potential approach, the MM → QM/MM perturbation converges in terms of energies, uncertainties, and overlap measures with two intermediate states, giving a precision of 0.5-0.9 kJ/mol for all eight transformations considered. On the other hand, the QM/MM-FEP approach requires 17-18 intermediate states, showing that the reference-potential approach is more effective. Previous calculations with single-step exponential averaging (i.e., entirely avoiding QM/MM simulations) required fewer QM/MM energy calculations, but they gave worse precision and involved approximations with an unclear effect on the results.</p>}},
  author       = {{Olsson, Martin A. and Ryde, Ulf}},
  issn         = {{1549-9618}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{2245--2253}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of Chemical Theory and Computation}},
  title        = {{Comparison of QM/MM Methods To Obtain Ligand-Binding Free Energies}},
  url          = {{http://dx.doi.org/10.1021/acs.jctc.6b01217}},
  doi          = {{10.1021/acs.jctc.6b01217}},
  volume       = {{13}},
  year         = {{2017}},
}