A Large-Scale Test of Free-Energy Simulation Estimates of Protein-Ligand Binding Affinities.
Mikulskis, Paulius LU ; Genheden, Samuel LU and Ryde, Ulf LU
(2014)
In Journal of Chemical Information and Modeling
54(10).
p.2794-2806
- Abstract
- We have performed a large-scale test of alchemical perturbation calculations with the Bennett acceptance-ratio (BAR) approach to estimate relative affinities for the binding of 107 ligands to 10 different proteins. Employing 20-Å truncated spherical systems and only one intermediate state in the perturbations, we obtain an error of less than 4 kJ/mol for 54% of the studied relative affinities and a precision of 0.5 kJ/mol on average. However, only four of the proteins gave acceptable errors, correlations, and rankings. The results could be improved by using nine intermediate states in the simulations or including the entire protein in the simulations using periodic boundary conditions. However, 27 of the calculated affinities still gave... (More)
- We have performed a large-scale test of alchemical perturbation calculations with the Bennett acceptance-ratio (BAR) approach to estimate relative affinities for the binding of 107 ligands to 10 different proteins. Employing 20-Å truncated spherical systems and only one intermediate state in the perturbations, we obtain an error of less than 4 kJ/mol for 54% of the studied relative affinities and a precision of 0.5 kJ/mol on average. However, only four of the proteins gave acceptable errors, correlations, and rankings. The results could be improved by using nine intermediate states in the simulations or including the entire protein in the simulations using periodic boundary conditions. However, 27 of the calculated affinities still gave errors of more than 4 kJ/mol, and for three of the proteins the results were not satisfactory. This shows that the performance of BAR calculations depends on the target protein and that several transformations gave poor results owing to limitations in the molecular-mechanics force field or the restricted sampling possible within a reasonable simulation time. Still, the BAR results are better than docking calculations for most of the proteins. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4699423
- author
- Mikulskis, Paulius
LU
; Genheden, Samuel
LU
and Ryde, Ulf
LU
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Chemical Information and Modeling
- volume
- 54
- issue
- 10
- pages
- 2794 - 2806
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:25264937
- wos:000343849600016
- scopus:84908225639
- pmid:25264937
- ISSN
- 1549-960X
- DOI
- 10.1021/ci5004027
- 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
- 1870140e-48ec-45a6-b9d3-2167f9fbfc8e (old id 4699423)
- date added to LUP
- 2016-04-01 09:58:14
- date last changed
- 2023-01-17 07:14:26
@article{1870140e-48ec-45a6-b9d3-2167f9fbfc8e,
abstract = {{We have performed a large-scale test of alchemical perturbation calculations with the Bennett acceptance-ratio (BAR) approach to estimate relative affinities for the binding of 107 ligands to 10 different proteins. Employing 20-Å truncated spherical systems and only one intermediate state in the perturbations, we obtain an error of less than 4 kJ/mol for 54% of the studied relative affinities and a precision of 0.5 kJ/mol on average. However, only four of the proteins gave acceptable errors, correlations, and rankings. The results could be improved by using nine intermediate states in the simulations or including the entire protein in the simulations using periodic boundary conditions. However, 27 of the calculated affinities still gave errors of more than 4 kJ/mol, and for three of the proteins the results were not satisfactory. This shows that the performance of BAR calculations depends on the target protein and that several transformations gave poor results owing to limitations in the molecular-mechanics force field or the restricted sampling possible within a reasonable simulation time. Still, the BAR results are better than docking calculations for most of the proteins.}},
author = {{Mikulskis, Paulius and Genheden, Samuel and Ryde, Ulf}},
issn = {{1549-960X}},
language = {{eng}},
number = {{10}},
pages = {{2794--2806}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of Chemical Information and Modeling}},
title = {{A Large-Scale Test of Free-Energy Simulation Estimates of Protein-Ligand Binding Affinities.}},
url = {{https://lup.lub.lu.se/search/files/1434939/4699505.pdf}},
doi = {{10.1021/ci5004027}},
volume = {{54}},
year = {{2014}},
}