Assessing the stability of free-energy perturbation calculations by performing variations in the method
Manzoni, Francesco LU and Ryde, Ulf LU
(2018)
In Journal of Computer-Aided Molecular Design
32(4).
p.529-536
- Abstract
We have calculated relative binding affinities for eight tetrafluorophenyl-triazole-thiogalactoside inhibitors of galectin-3 with the alchemical free-energy perturbation approach. We obtain a mean absolute deviation from experimental estimates of only 2–3 kJ/mol and a correlation coefficient (R2) of 0.5–0.8 for seven relative affinities spanning a range of up to 11 kJ/mol. We also studied the effect of using different methods to calculate the charges of the inhibitor and different sizes of the perturbed group (the atoms that are described by soft-core potentials and are allowed to have differing coordinates). However, the various approaches gave rather similar results and it is not possible to point out one approach as... (More)
We have calculated relative binding affinities for eight tetrafluorophenyl-triazole-thiogalactoside inhibitors of galectin-3 with the alchemical free-energy perturbation approach. We obtain a mean absolute deviation from experimental estimates of only 2–3 kJ/mol and a correlation coefficient (R2) of 0.5–0.8 for seven relative affinities spanning a range of up to 11 kJ/mol. We also studied the effect of using different methods to calculate the charges of the inhibitor and different sizes of the perturbed group (the atoms that are described by soft-core potentials and are allowed to have differing coordinates). However, the various approaches gave rather similar results and it is not possible to point out one approach as consistently and significantly better than the others. Instead, we suggest that such small and reasonable variations in the computational method can be used to check how stable the calculated results are and to obtain a more accurate estimate of the uncertainty than if performing only one calculation with a single computational setup.
(Less)
- author
- Manzoni, Francesco
LU
and Ryde, Ulf
LU
- organization
- publishing date
- 2018-03-13
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- AM1-BCC charges, Free-energy perturbation, Galectin-3, Independent simulations, Ligand-binding affinity, RESP charges
- in
- Journal of Computer-Aided Molecular Design
- volume
- 32
- issue
- 4
- pages
- 8 pages
- publisher
- Springer
- external identifiers
-
- scopus:85043703261
- pmid:29536221
- ISSN
- 0920-654X
- DOI
- 10.1007/s10822-018-0110-5
- language
- English
- LU publication?
- yes
- id
- 62a2b209-2729-493e-8c78-26959706d966
- date added to LUP
- 2018-03-27 09:46:59
- date last changed
- 2024-06-24 12:06:16
@article{62a2b209-2729-493e-8c78-26959706d966,
abstract = {{<p>We have calculated relative binding affinities for eight tetrafluorophenyl-triazole-thiogalactoside inhibitors of galectin-3 with the alchemical free-energy perturbation approach. We obtain a mean absolute deviation from experimental estimates of only 2–3 kJ/mol and a correlation coefficient (R<sup>2</sup>) of 0.5–0.8 for seven relative affinities spanning a range of up to 11 kJ/mol. We also studied the effect of using different methods to calculate the charges of the inhibitor and different sizes of the perturbed group (the atoms that are described by soft-core potentials and are allowed to have differing coordinates). However, the various approaches gave rather similar results and it is not possible to point out one approach as consistently and significantly better than the others. Instead, we suggest that such small and reasonable variations in the computational method can be used to check how stable the calculated results are and to obtain a more accurate estimate of the uncertainty than if performing only one calculation with a single computational setup.</p>}},
author = {{Manzoni, Francesco and Ryde, Ulf}},
issn = {{0920-654X}},
keywords = {{AM1-BCC charges; Free-energy perturbation; Galectin-3; Independent simulations; Ligand-binding affinity; RESP charges}},
language = {{eng}},
month = {{03}},
number = {{4}},
pages = {{529--536}},
publisher = {{Springer}},
series = {{Journal of Computer-Aided Molecular Design}},
title = {{Assessing the stability of free-energy perturbation calculations by performing variations in the method}},
url = {{http://dx.doi.org/10.1007/s10822-018-0110-5}},
doi = {{10.1007/s10822-018-0110-5}},
volume = {{32}},
year = {{2018}},
}