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Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods

Caldararu, Octav LU ; Olsson, Martin A. LU ; Misini Ignjatović, Majda LU ; Wang, Meiting and Ryde, Ulf LU (2018) In Journal of Computer-Aided Molecular Design 32(10). p.1027-1046
Abstract

We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates... (More)

We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R2) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R2 = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Density functional theory, Entropy, Free-energy perturbation, Ligand binding, Reference-potential with QM/MM sampling, Semiempirical methods
in
Journal of Computer-Aided Molecular Design
volume
32
issue
10
pages
1027 - 1046
publisher
Kluwer
external identifiers
  • scopus:85053538792
ISSN
0920-654X
DOI
10.1007/s10822-018-0158-2
language
English
LU publication?
yes
id
9ad4de3e-3bd1-472f-a891-d9450641d60c
date added to LUP
2018-10-22 11:56:05
date last changed
2019-01-14 08:43:27
@article{9ad4de3e-3bd1-472f-a891-d9450641d60c,
  abstract     = {<p>We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R<sup>2</sup>) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R<sup>2</sup> = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.</p>},
  author       = {Caldararu, Octav and Olsson, Martin A. and Misini Ignjatović, Majda and Wang, Meiting and Ryde, Ulf},
  issn         = {0920-654X},
  keyword      = {Density functional theory,Entropy,Free-energy perturbation,Ligand binding,Reference-potential with QM/MM sampling,Semiempirical methods},
  language     = {eng},
  month        = {09},
  number       = {10},
  pages        = {1027--1046},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods},
  url          = {http://dx.doi.org/10.1007/s10822-018-0158-2},
  volume       = {32},
  year         = {2018},
}