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

Olsson, Martin A. LU and Ryde, Ulf LU (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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author
organization
publishing date
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
external identifiers
  • scopus:85019167149
  • wos:000401221300033
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
2017-09-18 11:38:12
@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},
  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},
  volume       = {13},
  year         = {2017},
}