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Prediction of SAMPL4 host-guest binding affinities using funnel metadynamics

Hsiao, Ya-Wen and Söderhjelm, Pär LU (2014) In Journal of Computer-Aided Molecular Design 28(4). p.443-454
Abstract
Accurately predicting binding affinities between ligands and macromolecules has been a much sought-after goal. A tremendous amount of resources can be saved in the pharmaceutical industry through accurate binding-affinity prediction and hence correct decision-making for the drug discovery processes. Owing to the structural complexity of macromolecules, one of the issues in binding affinity prediction using molecular dynamics is the adequate sampling of the conformational space. Recently, the funnel metadynamics method (Limongelli et al. in Proc Natl Acad Sci USA 110: 6358, 2013) was developed to enhance the sampling of the ligand at the binding site as well as in the solvated state, and offer the possibility to predict the absolute binding... (More)
Accurately predicting binding affinities between ligands and macromolecules has been a much sought-after goal. A tremendous amount of resources can be saved in the pharmaceutical industry through accurate binding-affinity prediction and hence correct decision-making for the drug discovery processes. Owing to the structural complexity of macromolecules, one of the issues in binding affinity prediction using molecular dynamics is the adequate sampling of the conformational space. Recently, the funnel metadynamics method (Limongelli et al. in Proc Natl Acad Sci USA 110: 6358, 2013) was developed to enhance the sampling of the ligand at the binding site as well as in the solvated state, and offer the possibility to predict the absolute binding free energy. We apply funnel metadynamics to predict host-guest binding affinities for the cucurbit[7]uril host as part of the SAMPL4 blind challenge. Using total simulation times of 300-400 ns per ligand, we show that the errors due to inadequate sampling are below 1 kcal/mol. However, despite the large investment in terms of computational time, the results compared to experiment are not better than a random guess. As we obtain differences of up to 11 kcal/mol when switching between two commonly used force fields (with automatically generated parameters), we strongly believe that in the pursuit of accurate binding free energies a more careful force-field parametrization is needed to address this type of system. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Funnel metadynamics, Binding affinity, CGENFF, GAFF, NAMD
in
Journal of Computer-Aided Molecular Design
volume
28
issue
4
pages
443 - 454
publisher
Kluwer
external identifiers
  • wos:000337043500010
  • scopus:84902793534
ISSN
1573-4951
DOI
10.1007/s10822-014-9724-4
language
English
LU publication?
yes
id
53890904-19f8-4768-96f2-953ee3b1f94d (old id 4552281)
date added to LUP
2014-07-17 09:49:29
date last changed
2017-06-11 04:04:28
@article{53890904-19f8-4768-96f2-953ee3b1f94d,
  abstract     = {Accurately predicting binding affinities between ligands and macromolecules has been a much sought-after goal. A tremendous amount of resources can be saved in the pharmaceutical industry through accurate binding-affinity prediction and hence correct decision-making for the drug discovery processes. Owing to the structural complexity of macromolecules, one of the issues in binding affinity prediction using molecular dynamics is the adequate sampling of the conformational space. Recently, the funnel metadynamics method (Limongelli et al. in Proc Natl Acad Sci USA 110: 6358, 2013) was developed to enhance the sampling of the ligand at the binding site as well as in the solvated state, and offer the possibility to predict the absolute binding free energy. We apply funnel metadynamics to predict host-guest binding affinities for the cucurbit[7]uril host as part of the SAMPL4 blind challenge. Using total simulation times of 300-400 ns per ligand, we show that the errors due to inadequate sampling are below 1 kcal/mol. However, despite the large investment in terms of computational time, the results compared to experiment are not better than a random guess. As we obtain differences of up to 11 kcal/mol when switching between two commonly used force fields (with automatically generated parameters), we strongly believe that in the pursuit of accurate binding free energies a more careful force-field parametrization is needed to address this type of system.},
  author       = {Hsiao, Ya-Wen and Söderhjelm, Pär},
  issn         = {1573-4951},
  keyword      = {Funnel metadynamics,Binding affinity,CGENFF,GAFF,NAMD},
  language     = {eng},
  number       = {4},
  pages        = {443--454},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {Prediction of SAMPL4 host-guest binding affinities using funnel metadynamics},
  url          = {http://dx.doi.org/10.1007/s10822-014-9724-4},
  volume       = {28},
  year         = {2014},
}