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Are homology models sufficiently good for free-energy simulations?

Genheden, Samuel LU (2012) In Journal of Chemical Information and Modeling 52(11). p.3013-3021
Abstract
In this paper, I evaluate the usefulness of protein homology models in rigorous free-energy simulations to determine ligand affinities. Two templates were used to create models of the factor Xa protein and one template was used for dihydrofolate reductase from Plasmodium falciparum. Then, the relative free energies for several pairs of ligands were estimated using thermodynamic integration with the homology models as starting point of the simulation. These binding affinities were compared to affinities obtained when using published crystal structures as starting point of the simulations. Encouragingly, the differences between the affinities obtained when starting from either homology models or crystal structure were not statistical... (More)
In this paper, I evaluate the usefulness of protein homology models in rigorous free-energy simulations to determine ligand affinities. Two templates were used to create models of the factor Xa protein and one template was used for dihydrofolate reductase from Plasmodium falciparum. Then, the relative free energies for several pairs of ligands were estimated using thermodynamic integration with the homology models as starting point of the simulation. These binding affinities were compared to affinities obtained when using published crystal structures as starting point of the simulations. Encouragingly, the differences between the affinities obtained when starting from either homology models or crystal structure were not statistical significant for a majority of the considered pairs of ligands. Differences between 1 and 2 kJ/mol were observed for the dihydrofolate reductase ligands and differences between 0 and 8 kJ/mol were observed for the factor Xa ligands. The largest difference for factor Xa was caused by an erroneous modeling of a loop region close to two of the ligands, and it was only observed when using one of the templates. Therefore, it is advisible to always use more than one template when creating homology models if they should be used in free-energy simulations. (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
11
pages
3013 - 3021
publisher
The American Chemical Society
external identifiers
  • wos:000311461400021
  • pmid:23113602
  • scopus:84870021560
ISSN
1549-960X
DOI
10.1021/ci300349s
language
English
LU publication?
yes
id
c91f3007-2bc4-4cde-a568-bc6266130e77 (old id 3219346)
date added to LUP
2012-12-14 12:54:00
date last changed
2017-01-15 03:10:59
@article{c91f3007-2bc4-4cde-a568-bc6266130e77,
  abstract     = {In this paper, I evaluate the usefulness of protein homology models in rigorous free-energy simulations to determine ligand affinities. Two templates were used to create models of the factor Xa protein and one template was used for dihydrofolate reductase from Plasmodium falciparum. Then, the relative free energies for several pairs of ligands were estimated using thermodynamic integration with the homology models as starting point of the simulation. These binding affinities were compared to affinities obtained when using published crystal structures as starting point of the simulations. Encouragingly, the differences between the affinities obtained when starting from either homology models or crystal structure were not statistical significant for a majority of the considered pairs of ligands. Differences between 1 and 2 kJ/mol were observed for the dihydrofolate reductase ligands and differences between 0 and 8 kJ/mol were observed for the factor Xa ligands. The largest difference for factor Xa was caused by an erroneous modeling of a loop region close to two of the ligands, and it was only observed when using one of the templates. Therefore, it is advisible to always use more than one template when creating homology models if they should be used in free-energy simulations.},
  author       = {Genheden, Samuel},
  issn         = {1549-960X},
  language     = {eng},
  number       = {11},
  pages        = {3013--3021},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Information and Modeling},
  title        = {Are homology models sufficiently good for free-energy simulations?},
  url          = {http://dx.doi.org/10.1021/ci300349s},
  volume       = {52},
  year         = {2012},
}