Are homology models sufficiently good for free-energy simulations?
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3219346
- author
- Genheden, Samuel LU
- organization
- publishing date
- 2012
- 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 (ACS)
- external identifiers
-
- wos:000311461400021
- pmid:23113602
- scopus:84870021560
- pmid:23113602
- ISSN
- 1549-960X
- DOI
- 10.1021/ci300349s
- 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
- c91f3007-2bc4-4cde-a568-bc6266130e77 (old id 3219346)
- date added to LUP
- 2016-04-01 10:26:31
- date last changed
- 2023-01-02 04:32:18
@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 (ACS)}},
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}},
doi = {{10.1021/ci300349s}},
volume = {{52}},
year = {{2012}},
}