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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3287942
- author
- Genheden, Samuel
LU
; Kuhn, Oliver
; Mikulskis, Paulius
LU
; Hoffmann, Daniel
and Ryde, Ulf
LU
- organization
- publishing date
- 2012
- 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 (ACS)
- external identifiers
-
- wos:000308254200018
- scopus:84865511407
- pmid:22817270
- ISSN
- 1549-960X
- DOI
- 10.1021/ci3001919
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
- id
- 09748491-2aa4-4612-a0af-11c39489b783 (old id 3287942)
- date added to LUP
- 2016-04-01 10:09:35
- date last changed
- 2023-04-18 22:08:45
@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 (ACS)}},
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 = {{https://lup.lub.lu.se/search/files/1614610/3412388.pdf}},
doi = {{10.1021/ci3001919}},
volume = {{52}},
year = {{2012}},
}