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

Caldararu, O., Olsson, M. A., Riplinger, C., Neese, F., & Ryde, U. (2017). Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T). Journal of Computer-Aided Molecular Design, 31(1), 87-106. doi:10.1007/s10822-016-9957-5.

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Caldararu, Octav1, Author
Olsson, Martin A.1, Author
Riplinger, Christoph2, Author              
Neese, Frank2, Author              
Ryde, Ulf1, Author
1Department of Theoretical Chemistry, Chemical Centre, Lund University, P. O. Box 124, 221 00, Lund, Sweden, ou_persistent22              
2Research Department Neese, Max Planck Institute for Chemical Energy Conversion, Max Planck Society, ou_3023886              


Free keywords: Ligand-binding affinities; Host-guest-systems; Deinsity-functional theory; Dispersion corrections; COSMO-RS; DLPNO-CCSD(T); SAMPL5
 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 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.


Language(s): eng - English
 Dates: 2016-06-202016-09-062017-01-01
 Publication Status: Published in print
 Pages: 20
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1007/s10822-016-9957-5
 Degree: -



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Title: Journal of Computer-Aided Molecular Design
  Abbreviation : J. Comput.-Aided Mol. Des.
Source Genre: Journal
Publ. Info: Switzerland : Springer International Publishing
Pages: - Volume / Issue: 31 (1) Sequence Number: - Start / End Page: 87 - 106 Identifier: ISSN: 0920-654X
CoNE: https://pure.mpg.de/cone/journals/resource/954925564670