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Comparison of end-point continuum-solvation methods for the calculation of protein-ligand binding free energies.

Genheden, Samuel LU and Ryde, Ulf LU (2012) In Proteins 80(5). p.1326-1342
Abstract
We have compared the predictions of ligand-binding affinities from several methods based on end-point molecular dynamics simulations and continuum solvation, i.e. methods related to MM/PBSA (molecular mechanics combined with Poisson-Boltzmann and surface area solvation). Two continuum-solvation models were considered, viz. the Poisson-Boltzmann (PB) and generalised Born (GB) approaches. The non-electrostatic energies were also obtained in two different ways, viz. either from the sum of the bonded, van der Waals, non-polar solvation energies, and entropy terms (as in MM/PBSA), or from the scaled protein-ligand van der Waals interaction energy (as in the linear interaction energy approach, LIE). Three different approaches to calculate... (More)
We have compared the predictions of ligand-binding affinities from several methods based on end-point molecular dynamics simulations and continuum solvation, i.e. methods related to MM/PBSA (molecular mechanics combined with Poisson-Boltzmann and surface area solvation). Two continuum-solvation models were considered, viz. the Poisson-Boltzmann (PB) and generalised Born (GB) approaches. The non-electrostatic energies were also obtained in two different ways, viz. either from the sum of the bonded, van der Waals, non-polar solvation energies, and entropy terms (as in MM/PBSA), or from the scaled protein-ligand van der Waals interaction energy (as in the linear interaction energy approach, LIE). Three different approaches to calculate electrostatic energies were tested, viz. the sum of electrostatic interaction energies and polar solvation energies, obtained either from a single simulation of the complex or from three independent simulations of the complex, the free protein, and the free ligand, or the linear-response approximation (LRA). Moreover, we investigated the effect of scaling the electrostatic interactions by an effective internal dielectric constant of the protein (ε(int) ). All these methods were tested on the binding of seven biotin analogues to avidin and nine 3-amidinobenzyl-1H-indole-2-carboxamide inhibitors to factor Xa. For avidin, the best results were obtained with a combination of the LIE non-electrostatic energies with the MM+GB electrostatic energies from a single simulation, using ε(int) = 4. For fXa, standard MM/GBSA, based on one simulation and using ε(int) = 4-10 gave the best result. The optimum internal dielectric constant seems to be slightly higher with PB than with GB solvation. Proteins 2012. © 2012 Wiley-Liss, Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proteins
volume
80
issue
5
pages
1326 - 1342
publisher
John Wiley & Sons
external identifiers
  • wos:000302541900007
  • pmid:22274991
  • scopus:84859438966
ISSN
0887-3585
DOI
10.1002/prot.24029
language
English
LU publication?
yes
id
01a5faa7-8366-4afc-8d50-0cb58bbb7946 (old id 2336016)
date added to LUP
2012-02-07 16:59:03
date last changed
2017-10-22 04:01:12
@article{01a5faa7-8366-4afc-8d50-0cb58bbb7946,
  abstract     = {We have compared the predictions of ligand-binding affinities from several methods based on end-point molecular dynamics simulations and continuum solvation, i.e. methods related to MM/PBSA (molecular mechanics combined with Poisson-Boltzmann and surface area solvation). Two continuum-solvation models were considered, viz. the Poisson-Boltzmann (PB) and generalised Born (GB) approaches. The non-electrostatic energies were also obtained in two different ways, viz. either from the sum of the bonded, van der Waals, non-polar solvation energies, and entropy terms (as in MM/PBSA), or from the scaled protein-ligand van der Waals interaction energy (as in the linear interaction energy approach, LIE). Three different approaches to calculate electrostatic energies were tested, viz. the sum of electrostatic interaction energies and polar solvation energies, obtained either from a single simulation of the complex or from three independent simulations of the complex, the free protein, and the free ligand, or the linear-response approximation (LRA). Moreover, we investigated the effect of scaling the electrostatic interactions by an effective internal dielectric constant of the protein (ε(int) ). All these methods were tested on the binding of seven biotin analogues to avidin and nine 3-amidinobenzyl-1H-indole-2-carboxamide inhibitors to factor Xa. For avidin, the best results were obtained with a combination of the LIE non-electrostatic energies with the MM+GB electrostatic energies from a single simulation, using ε(int) = 4. For fXa, standard MM/GBSA, based on one simulation and using ε(int) = 4-10 gave the best result. The optimum internal dielectric constant seems to be slightly higher with PB than with GB solvation. Proteins 2012. © 2012 Wiley-Liss, Inc.},
  author       = {Genheden, Samuel and Ryde, Ulf},
  issn         = {0887-3585},
  language     = {eng},
  number       = {5},
  pages        = {1326--1342},
  publisher    = {John Wiley & Sons},
  series       = {Proteins},
  title        = {Comparison of end-point continuum-solvation methods for the calculation of protein-ligand binding free energies.},
  url          = {http://dx.doi.org/10.1002/prot.24029},
  volume       = {80},
  year         = {2012},
}