Advanced

An improved method to predict the entropy term with the MM/PBSA approach.

Kongsted, Jacob LU and Ryde, Ulf LU (2009) In Journal of Computer-Aided Molecular Design 23. p.63-71
Abstract
A method is suggested to calculate improved entropies within the MM/PBSA approach (molecular mechanics combined with Poisson-Boltzmann and surface area calculations) to estimate protein-ligand binding affinities. In the conventional approach, the protein is truncated outside ~8 A from the ligand. This system is freely minimised using a distance-dependent dielectric constant (to simulate the removed protein and solvent). However, this can lead to extensive changes in the molecular geometry, giving rise to a large standard deviation in this term. In our new approach, we introduce a buffer region ~4 A outside the truncated protein (including solvent molecules) and keep it fixed during the minimisation. Thereby, we reduce the standard... (More)
A method is suggested to calculate improved entropies within the MM/PBSA approach (molecular mechanics combined with Poisson-Boltzmann and surface area calculations) to estimate protein-ligand binding affinities. In the conventional approach, the protein is truncated outside ~8 A from the ligand. This system is freely minimised using a distance-dependent dielectric constant (to simulate the removed protein and solvent). However, this can lead to extensive changes in the molecular geometry, giving rise to a large standard deviation in this term. In our new approach, we introduce a buffer region ~4 A outside the truncated protein (including solvent molecules) and keep it fixed during the minimisation. Thereby, we reduce the standard deviation by a factor of 2-4, ensuring that the entropy term no longer limits the precision of the MM/PBSA predictions. The new method is tested for the binding of seven biotin analogues to avidin, eight amidinobenzyl-indole-carboxamide inhibitors to factor Xa, and two substrates to cytochrome P450 3A4 and 2C9. It is shown that it gives more stable results and often improved predictions of the relative binding affinities. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cytochrome P450, Factor Xa, Avidin, MM/PBSA, Entropy
in
Journal of Computer-Aided Molecular Design
volume
23
pages
63 - 71
publisher
Kluwer
external identifiers
  • wos:000262124900001
  • pmid:18781280
  • scopus:58149327312
ISSN
1573-4951
DOI
10.1007/s10822-008-9238-z
language
English
LU publication?
yes
id
d1ba6781-2b11-4b6e-af87-e4e54f9e904c (old id 1243216)
date added to LUP
2008-10-16 17:33:01
date last changed
2017-12-10 04:16:56
@article{d1ba6781-2b11-4b6e-af87-e4e54f9e904c,
  abstract     = {A method is suggested to calculate improved entropies within the MM/PBSA approach (molecular mechanics combined with Poisson-Boltzmann and surface area calculations) to estimate protein-ligand binding affinities. In the conventional approach, the protein is truncated outside ~8 A from the ligand. This system is freely minimised using a distance-dependent dielectric constant (to simulate the removed protein and solvent). However, this can lead to extensive changes in the molecular geometry, giving rise to a large standard deviation in this term. In our new approach, we introduce a buffer region ~4 A outside the truncated protein (including solvent molecules) and keep it fixed during the minimisation. Thereby, we reduce the standard deviation by a factor of 2-4, ensuring that the entropy term no longer limits the precision of the MM/PBSA predictions. The new method is tested for the binding of seven biotin analogues to avidin, eight amidinobenzyl-indole-carboxamide inhibitors to factor Xa, and two substrates to cytochrome P450 3A4 and 2C9. It is shown that it gives more stable results and often improved predictions of the relative binding affinities.},
  author       = {Kongsted, Jacob and Ryde, Ulf},
  issn         = {1573-4951},
  keyword      = {Cytochrome P450,Factor Xa,Avidin,MM/PBSA,Entropy},
  language     = {eng},
  pages        = {63--71},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {An improved method to predict the entropy term with the MM/PBSA approach.},
  url          = {http://dx.doi.org/10.1007/s10822-008-9238-z},
  volume       = {23},
  year         = {2009},
}