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Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model.

Genheden, Samuel; Ryde, Ulf LU and Söderhjelm, Pär LU (2015) In Journal of Computational Chemistry 36(28). p.2114-2124
Abstract
The most general way to improve the accuracy of binding-affinity calculations for protein-ligand systems is to use quantum-mechanical (QM) methods together with rigorous alchemical-perturbation (AP) methods. We explore this approach by calculating the relative binding free energy of two synthetic disaccharides binding to galectin-3 at a reasonably high QM level (dispersion-corrected density functional theory with a triple-zeta basis set) and with a sufficiently large QM system to include all short-range interactions with the ligand (744-748 atoms). The rest of the protein is treated as a collection of atomic multipoles (up to quadrupoles) and polarizabilities. Several methods for evaluating the binding free energy from the 3600 QM... (More)
The most general way to improve the accuracy of binding-affinity calculations for protein-ligand systems is to use quantum-mechanical (QM) methods together with rigorous alchemical-perturbation (AP) methods. We explore this approach by calculating the relative binding free energy of two synthetic disaccharides binding to galectin-3 at a reasonably high QM level (dispersion-corrected density functional theory with a triple-zeta basis set) and with a sufficiently large QM system to include all short-range interactions with the ligand (744-748 atoms). The rest of the protein is treated as a collection of atomic multipoles (up to quadrupoles) and polarizabilities. Several methods for evaluating the binding free energy from the 3600 QM calculations are investigated in terms of stability and accuracy. In particular, methods using QM calculations only at the endpoints of the transformation are compared with the recently proposed non-Boltzmann Bennett acceptance ratio (NBB) method that uses QM calculations at several stages of the transformation. Unfortunately, none of the rigorous approaches give sufficient statistical precision. However, a novel approximate method, involving the direct use of QM energies in the Bennett acceptance ratio method, gives similar results as NBB but with better precision, ∼3 kJ/mol. The statistical error can be further reduced by performing a greater number of QM calculations. © 2015 Wiley Periodicals, Inc. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Computational Chemistry
volume
36
issue
28
pages
2114 - 2124
publisher
John Wiley & Sons
external identifiers
  • pmid:26280564
  • wos:000363700500004
  • scopus:84939537729
ISSN
1096-987X
DOI
10.1002/jcc.24048
language
English
LU publication?
yes
id
aa85e56f-8239-46e7-8117-ac32c0a9c1cb (old id 7840770)
date added to LUP
2015-09-13 20:42:48
date last changed
2017-05-28 03:14:56
@article{aa85e56f-8239-46e7-8117-ac32c0a9c1cb,
  abstract     = {The most general way to improve the accuracy of binding-affinity calculations for protein-ligand systems is to use quantum-mechanical (QM) methods together with rigorous alchemical-perturbation (AP) methods. We explore this approach by calculating the relative binding free energy of two synthetic disaccharides binding to galectin-3 at a reasonably high QM level (dispersion-corrected density functional theory with a triple-zeta basis set) and with a sufficiently large QM system to include all short-range interactions with the ligand (744-748 atoms). The rest of the protein is treated as a collection of atomic multipoles (up to quadrupoles) and polarizabilities. Several methods for evaluating the binding free energy from the 3600 QM calculations are investigated in terms of stability and accuracy. In particular, methods using QM calculations only at the endpoints of the transformation are compared with the recently proposed non-Boltzmann Bennett acceptance ratio (NBB) method that uses QM calculations at several stages of the transformation. Unfortunately, none of the rigorous approaches give sufficient statistical precision. However, a novel approximate method, involving the direct use of QM energies in the Bennett acceptance ratio method, gives similar results as NBB but with better precision, ∼3 kJ/mol. The statistical error can be further reduced by performing a greater number of QM calculations. © 2015 Wiley Periodicals, Inc.},
  author       = {Genheden, Samuel and Ryde, Ulf and Söderhjelm, Pär},
  issn         = {1096-987X},
  language     = {eng},
  number       = {28},
  pages        = {2114--2124},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Computational Chemistry},
  title        = {Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model.},
  url          = {http://dx.doi.org/10.1002/jcc.24048},
  volume       = {36},
  year         = {2015},
}