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

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 u...

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Autores principales: Caldararu, Octav, Olsson, Martin A., Riplinger, Christoph, Neese, Frank, Ryde, Ulf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239813/
https://www.ncbi.nlm.nih.gov/pubmed/27600554
http://dx.doi.org/10.1007/s10822-016-9957-5
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author Caldararu, Octav
Olsson, Martin A.
Riplinger, Christoph
Neese, Frank
Ryde, Ulf
author_facet Caldararu, Octav
Olsson, Martin A.
Riplinger, Christoph
Neese, Frank
Ryde, Ulf
author_sort Caldararu, Octav
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-016-9957-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-52398132017-01-31 Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T) Caldararu, Octav Olsson, Martin A. Riplinger, Christoph Neese, Frank Ryde, Ulf J Comput Aided Mol Des Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10822-016-9957-5) contains supplementary material, which is available to authorized users. Springer International Publishing 2016-09-06 2017 /pmc/articles/PMC5239813/ /pubmed/27600554 http://dx.doi.org/10.1007/s10822-016-9957-5 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Article
Caldararu, Octav
Olsson, Martin A.
Riplinger, Christoph
Neese, Frank
Ryde, Ulf
Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)
title Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)
title_full Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)
title_fullStr Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)
title_full_unstemmed Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)
title_short Binding free energies in the SAMPL5 octa-acid host–guest challenge calculated with DFT-D3 and CCSD(T)
title_sort binding free energies in the sampl5 octa-acid host–guest challenge calculated with dft-d3 and ccsd(t)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5239813/
https://www.ncbi.nlm.nih.gov/pubmed/27600554
http://dx.doi.org/10.1007/s10822-016-9957-5
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