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The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant

Genheden, Samuel LU ; Kuhn, Oliver; Mikulskis, Paulius LU ; Hoffmann, Daniel and Ryde, Ulf LU (2012) In Journal of Chemical Information and Modeling 52(8). p.2079-2088
Abstract
We have performed a systematic study of the entropy term in the MM/GBSA (molecular Mechanics combined with generalized Born and surface area solvation) approach to calculate ligand-binding affinities The entropies are calculated by a normal mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with. distances. larger than 8-16 angstrom to the ligand, including a 4 angstrom shell of fixed protein residues and water molecules,... (More)
We have performed a systematic study of the entropy term in the MM/GBSA (molecular Mechanics combined with generalized Born and surface area solvation) approach to calculate ligand-binding affinities The entropies are calculated by a normal mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with. distances. larger than 8-16 angstrom to the ligand, including a 4 angstrom shell of fixed protein residues and water molecules, change the absolute entropies by 1-5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7-1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the Whole protein within statistical uncertainty (172 kJ/mol). We have also tested to use a distance dependent dielectric constant in the minimization and. frequency calculation (epsilon = 4r), but it typically gives slightly different entropies and poorer binding, affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 angstrom) and epsilon =1 Such an approach also gives an improved precision for the calculated binding free energies. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Information and Modeling
volume
52
issue
8
pages
2079 - 2088
publisher
The American Chemical Society
external identifiers
  • wos:000308254200018
  • scopus:84865511407
ISSN
1549-960X
DOI
10.1021/ci3001919
language
English
LU publication?
yes
id
09748491-2aa4-4612-a0af-11c39489b783 (old id 3287942)
date added to LUP
2012-12-19 11:38:19
date last changed
2017-11-05 03:07:04
@article{09748491-2aa4-4612-a0af-11c39489b783,
  abstract     = {We have performed a systematic study of the entropy term in the MM/GBSA (molecular Mechanics combined with generalized Born and surface area solvation) approach to calculate ligand-binding affinities The entropies are calculated by a normal mode analysis of harmonic frequencies from minimized snapshots of molecular dynamics simulations. For computational reasons, these calculations have normally been performed on truncated systems. We have studied the binding of eight inhibitors of blood clotting factor Xa, nine ligands of ferritin, and two ligands of HIV-1 protease and show that removing protein residues with. distances. larger than 8-16 angstrom to the ligand, including a 4 angstrom shell of fixed protein residues and water molecules, change the absolute entropies by 1-5 kJ/mol on average. However, the change is systematic, so relative entropies for different ligands change by only 0.7-1.6 kJ/mol on average. Consequently, entropies from truncated systems give relative binding affinities that are identical to those obtained for the Whole protein within statistical uncertainty (172 kJ/mol). We have also tested to use a distance dependent dielectric constant in the minimization and. frequency calculation (epsilon = 4r), but it typically gives slightly different entropies and poorer binding, affinities. Therefore, we recommend entropies calculated with the smallest truncation radius (8 angstrom) and epsilon =1 Such an approach also gives an improved precision for the calculated binding free energies.},
  author       = {Genheden, Samuel and Kuhn, Oliver and Mikulskis, Paulius and Hoffmann, Daniel and Ryde, Ulf},
  issn         = {1549-960X},
  language     = {eng},
  number       = {8},
  pages        = {2079--2088},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Information and Modeling},
  title        = {The Normal-Mode Entropy in the MM/GBSA Method: Effect of System Truncation, Buffer Region, and Dielectric Constant},
  url          = {http://dx.doi.org/10.1021/ci3001919},
  volume       = {52},
  year         = {2012},
}