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Improving the Efficiency of Protein-Ligand Binding Free-Energy Calculations by System Truncation

Genheden, Samuel LU and Ryde, Ulf LU (2012) In Journal of Chemical Theory and Computation 8(4). p.1449-1458
Abstract
We have studied whether the efficiency of alchemical free-energy calculations with the Bennett acceptance ratio method of protein-ligand binding energies can be improved by simulating only part of the protein. To this end, we solvated the full protein in a spherical droplet with a radius of 46 angstrom, surrounded by a vacuum. Then, we systematically reduced the size of the droplet and at the same time ignored protein residues that were outside the droplet. Radii of 40-15 angstrom were tested. Ten inhibitors of the blood clotting factor Xa were studied, and the results were compared to an earlier study in which the protein was solvated in a periodic box, showing complete agreement between the two sets of calculations within statistical... (More)
We have studied whether the efficiency of alchemical free-energy calculations with the Bennett acceptance ratio method of protein-ligand binding energies can be improved by simulating only part of the protein. To this end, we solvated the full protein in a spherical droplet with a radius of 46 angstrom, surrounded by a vacuum. Then, we systematically reduced the size of the droplet and at the same time ignored protein residues that were outside the droplet. Radii of 40-15 angstrom were tested. Ten inhibitors of the blood clotting factor Xa were studied, and the results were compared to an earlier study in which the protein was solvated in a periodic box, showing complete agreement between the two sets of calculations within statistical uncertainty. We then show that the simulated system can be truncated down to 15 angstrom, without changing the calculated affinities by more than 0.5 kJ/mol on average (maximum difference of 1.4 kJ/mol). Moreover, we show that reducing the number of intermediate states in the calculations from eleven to three gave deviations that, on average, were only 0.5 kJ/mol (maximum of 1.4 kJ/mol). Together, these results show that truncation is an appropriate way to improve the efficiency of free-energy calculations for small mutations that preserve the net charge of the ligand. in fact, each calculation of a relative binding affinity requires only six simulations, each of which takes similar to 15 CPU h of computation on a single processor. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
8
issue
4
pages
1449 - 1458
publisher
The American Chemical Society
external identifiers
  • wos:000302487700030
  • scopus:84859619156
ISSN
1549-9618
DOI
10.1021/ct200853g
language
English
LU publication?
yes
id
69813152-eee8-4181-9b20-66378d1e34bd (old id 2574864)
date added to LUP
2012-06-04 12:49:44
date last changed
2017-01-29 03:04:27
@article{69813152-eee8-4181-9b20-66378d1e34bd,
  abstract     = {We have studied whether the efficiency of alchemical free-energy calculations with the Bennett acceptance ratio method of protein-ligand binding energies can be improved by simulating only part of the protein. To this end, we solvated the full protein in a spherical droplet with a radius of 46 angstrom, surrounded by a vacuum. Then, we systematically reduced the size of the droplet and at the same time ignored protein residues that were outside the droplet. Radii of 40-15 angstrom were tested. Ten inhibitors of the blood clotting factor Xa were studied, and the results were compared to an earlier study in which the protein was solvated in a periodic box, showing complete agreement between the two sets of calculations within statistical uncertainty. We then show that the simulated system can be truncated down to 15 angstrom, without changing the calculated affinities by more than 0.5 kJ/mol on average (maximum difference of 1.4 kJ/mol). Moreover, we show that reducing the number of intermediate states in the calculations from eleven to three gave deviations that, on average, were only 0.5 kJ/mol (maximum of 1.4 kJ/mol). Together, these results show that truncation is an appropriate way to improve the efficiency of free-energy calculations for small mutations that preserve the net charge of the ligand. in fact, each calculation of a relative binding affinity requires only six simulations, each of which takes similar to 15 CPU h of computation on a single processor.},
  author       = {Genheden, Samuel and Ryde, Ulf},
  issn         = {1549-9618},
  language     = {eng},
  number       = {4},
  pages        = {1449--1458},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Improving the Efficiency of Protein-Ligand Binding Free-Energy Calculations by System Truncation},
  url          = {http://dx.doi.org/10.1021/ct200853g},
  volume       = {8},
  year         = {2012},
}