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Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)

Caldararu, Octav LU ; Olsson, Martin A. LU ; Riplinger, Christoph; Neese, Frank and Ryde, Ulf LU (2017) In Journal of Computer-Aided Molecular Design 31(1). p.87-106
Abstract

We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the... (More)

We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the effect of a restricted molecular dynamics sampling of structures was tested. Finally, we tried to improve the energies by using the DLPNO–CCSD(T) approach. Unfortunately, results of quite poor quality were obtained, with no correlation to the experimental data, systematically too positive affinities (by ~50 kJ/mol) and a mean absolute error (after removal of the systematic error) of 11–16 kJ/mol. DLPNO–CCSD(T) did not improve the results, so the accuracy is not limited by the energy function. Instead, four likely sources of errors were identified: first, the minimised structures were often incorrect, owing to the omission of explicit solvent. They could be partly improved by performing the minimisations in a continuum solvent with four water molecules around the charged groups of the ligands. Second, some ligands could bind in several different conformations, requiring sampling of reasonable structures. Third, there is an indication the continuum-solvation model has problems to accurately describe the binding of both the negatively and positively charged guest molecules. Fourth, different methods to calculate the thermostatistical corrections gave results that differed by up to 30 kJ/mol and there is an indication that HF-3c overestimates the entropy term. In conclusion, it is a challenge to calculate binding affinities for this octa-acid system with quantum–mechanical methods.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
COSMO-RS, Density-functional theory, Dispersion corrections, DLPNO–CCSD(T), Host–guest systems, Ligand-binding affinities, SAMPL5
in
Journal of Computer-Aided Molecular Design
volume
31
issue
1
pages
87 - 106
publisher
Kluwer
external identifiers
  • scopus:84986255660
  • wos:000392326500008
ISSN
0920-654X
DOI
10.1007/s10822-016-9957-5
language
English
LU publication?
yes
id
ca53bb69-639b-410e-8758-706190ce3ac3
date added to LUP
2016-11-08 16:40:33
date last changed
2018-01-07 11:34:24
@article{ca53bb69-639b-410e-8758-706190ce3ac3,
  abstract     = {<p>We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the effect of a restricted molecular dynamics sampling of structures was tested. Finally, we tried to improve the energies by using the DLPNO–CCSD(T) approach. Unfortunately, results of quite poor quality were obtained, with no correlation to the experimental data, systematically too positive affinities (by ~50 kJ/mol) and a mean absolute error (after removal of the systematic error) of 11–16 kJ/mol. DLPNO–CCSD(T) did not improve the results, so the accuracy is not limited by the energy function. Instead, four likely sources of errors were identified: first, the minimised structures were often incorrect, owing to the omission of explicit solvent. They could be partly improved by performing the minimisations in a continuum solvent with four water molecules around the charged groups of the ligands. Second, some ligands could bind in several different conformations, requiring sampling of reasonable structures. Third, there is an indication the continuum-solvation model has problems to accurately describe the binding of both the negatively and positively charged guest molecules. Fourth, different methods to calculate the thermostatistical corrections gave results that differed by up to 30 kJ/mol and there is an indication that HF-3c overestimates the entropy term. In conclusion, it is a challenge to calculate binding affinities for this octa-acid system with quantum–mechanical methods.</p>},
  author       = {Caldararu, Octav and Olsson, Martin A. and Riplinger, Christoph and Neese, Frank and Ryde, Ulf},
  issn         = {0920-654X},
  keyword      = {COSMO-RS,Density-functional theory,Dispersion corrections,DLPNO–CCSD(T),Host–guest systems,Ligand-binding affinities,SAMPL5},
  language     = {eng},
  number       = {1},
  pages        = {87--106},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)},
  url          = {http://dx.doi.org/10.1007/s10822-016-9957-5},
  volume       = {31},
  year         = {2017},
}