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Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host-guest binding energies.

Mikulskis, Paulius LU ; Cioloboc, Daniela; Andrejić, Milica; Khare, Sakshi; Brorsson, Joakim LU ; Genheden, Samuel LU ; Mata, Ricardo A; Söderhjelm, Pär LU and Ryde, Ulf LU (2014) In Journal of Computer-Aided Molecular Design 28(4). p.375-400
Abstract
We have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R (2)) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800... (More)
We have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R (2)) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800 density-functional theory (DFT) calculations for selected snapshots and the non-Boltzmann Bennett acceptance-ratio method, but this led to much worse results, probably because of a too large difference between the MM and DFT potential-energy functions. Third, we tried to calculate absolute affinities using minimised DFT structures. This gave intermediate-quality results with MADs of 5-9 kJ/mol and R (2) = 0.6-0.8, depending on how the structures were obtained. Finally, we tried to improve these results using local coupled-cluster calculations with single and double excitations, and non-iterative perturbative treatment of triple excitations (LCCSD(T0)), employing the polarisable multipole interactions with supermolecular pairs approach. Unfortunately, this only degraded the predictions, probably because of a mismatch between the solvation energies obtained at the DFT and LCCSD(T0) levels. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Computer-Aided Molecular Design
volume
28
issue
4
pages
375 - 400
publisher
Kluwer
external identifiers
  • pmid:24700414
  • wos:000337043500006
  • scopus:84902805310
ISSN
1573-4951
DOI
10.1007/s10822-014-9739-x
language
English
LU publication?
yes
id
4fa68200-2d3c-4343-b6eb-1b22501294b6 (old id 4430841)
date added to LUP
2014-05-07 17:19:11
date last changed
2017-11-05 03:13:37
@article{4fa68200-2d3c-4343-b6eb-1b22501294b6,
  abstract     = {We have estimated free energies for the binding of nine cyclic carboxylate guest molecules to the octa-acid host in the SAMPL4 blind-test challenge with four different approaches. First, we used standard free-energy perturbation calculations of relative binding affinities, performed at the molecular-mechanics (MM) level with TIP3P waters, the GAFF force field, and two different sets of charges for the host and the guest, obtained either with the restrained electrostatic potential or AM1-BCC methods. Both charge sets give good and nearly identical results, with a mean absolute deviation (MAD) of 4 kJ/mol and a correlation coefficient (R (2)) of 0.8 compared to experimental results. Second, we tried to improve these predictions with 28,800 density-functional theory (DFT) calculations for selected snapshots and the non-Boltzmann Bennett acceptance-ratio method, but this led to much worse results, probably because of a too large difference between the MM and DFT potential-energy functions. Third, we tried to calculate absolute affinities using minimised DFT structures. This gave intermediate-quality results with MADs of 5-9 kJ/mol and R (2) = 0.6-0.8, depending on how the structures were obtained. Finally, we tried to improve these results using local coupled-cluster calculations with single and double excitations, and non-iterative perturbative treatment of triple excitations (LCCSD(T0)), employing the polarisable multipole interactions with supermolecular pairs approach. Unfortunately, this only degraded the predictions, probably because of a mismatch between the solvation energies obtained at the DFT and LCCSD(T0) levels.},
  author       = {Mikulskis, Paulius and Cioloboc, Daniela and Andrejić, Milica and Khare, Sakshi and Brorsson, Joakim and Genheden, Samuel and Mata, Ricardo A and Söderhjelm, Pär and Ryde, Ulf},
  issn         = {1573-4951},
  language     = {eng},
  number       = {4},
  pages        = {375--400},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Free-energy perturbation and quantum mechanical study of SAMPL4 octa-acid host-guest binding energies.},
  url          = {http://dx.doi.org/10.1007/s10822-014-9739-x},
  volume       = {28},
  year         = {2014},
}