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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)
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author
organization
publishing date
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
external identifiers
  • pmid:25264937
  • wos:000343849600016
  • scopus:84908225639
ISSN
1549-960X
DOI
10.1021/ci5004027
language
English
LU publication?
yes
id
1870140e-48ec-45a6-b9d3-2167f9fbfc8e (old id 4699423)
date added to LUP
2014-10-22 08:20:28
date last changed
2017-09-24 03:03:48
@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},
  series       = {Journal of Chemical Information and Modeling},
  title        = {A Large-Scale Test of Free-Energy Simulation Estimates of Protein-Ligand Binding Affinities.},
  url          = {http://dx.doi.org/10.1021/ci5004027},
  volume       = {54},
  year         = {2014},
}