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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/7840770
- author
- Genheden, Samuel
; Ryde, Ulf
LU
and Söderhjelm, Pär
LU
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Computational Chemistry
- volume
- 36
- issue
- 28
- pages
- 2114 - 2124
- publisher
- John Wiley & Sons Inc.
- external identifiers
-
- pmid:26280564
- wos:000363700500004
- scopus:84939537729
- pmid:26280564
- ISSN
- 1096-987X
- DOI
- 10.1002/jcc.24048
- 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), Biophysical Chemistry (LTH) (011001011)
- id
- aa85e56f-8239-46e7-8117-ac32c0a9c1cb (old id 7840770)
- date added to LUP
- 2016-04-01 10:33:51
- date last changed
- 2023-02-20 03:03:39
@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 Inc.}},
series = {{Journal of Computational Chemistry}},
title = {{Binding affinities by alchemical perturbation using QM/MM with a large QM system and polarizable MM model.}},
url = {{https://lup.lub.lu.se/search/files/1949072/8508848.pdf}},
doi = {{10.1002/jcc.24048}},
volume = {{36}},
year = {{2015}},
}