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Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations

Wang, Meiting; Mei, Ye and Ryde, Ulf LU (2018) In Journal of Chemical Theory and Computation 14. p.6613-6613
Abstract
Calculating binding free energies with quan-
tum-mechanical (QM) methods is notoriously time-consum-
ing. In this work, we studied whether such calculations can be
accelerated by using nonequilibrium (NE) molecular
dynamics simulations employing Jarzynski’s equality. We
studied the binding of nine cyclic carboxylate ligands to the
octa-acid deep-cavity host from the SAMPL4 challenge with
the reference potential approach. The binding free energies
were first calculated at the molecular mechanics (MM) level
with free energy perturbation using the generalized Amber
force field with restrained electrostatic potential charges for
the host and the ligands. Then the free energy corrections for going... (More)
Calculating binding free energies with quan-
tum-mechanical (QM) methods is notoriously time-consum-
ing. In this work, we studied whether such calculations can be
accelerated by using nonequilibrium (NE) molecular
dynamics simulations employing Jarzynski’s equality. We
studied the binding of nine cyclic carboxylate ligands to the
octa-acid deep-cavity host from the SAMPL4 challenge with
the reference potential approach. The binding free energies
were first calculated at the molecular mechanics (MM) level
with free energy perturbation using the generalized Amber
force field with restrained electrostatic potential charges for
the host and the ligands. Then the free energy corrections for going from the MM Hamiltonian to a hybrid QM/MM Hamiltonian were estimated by averaging over many short NE molecular dynamics simulations. In the QM/MM calculations, the ligand was described at the semiempirical PM6-DH+ level. We show that this approach yields MM → QM/MM free energy corrections that agree with those from other approaches within statistical uncertainties. The desired precision can be obtained by running a proper number of independent NE simulations. For the systems studied in this work, a total simulation length of 20 ps was appropriate for most of the ligands, and 36−324 simulations were necessary in order to reach a precision of 0.3 kJ/ mol. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
14
pages
6622 pages
publisher
The American Chemical Society
external identifiers
  • scopus:85053553522
ISSN
1549-9618
DOI
10.1021/acs.jctc.8b00685
language
English
LU publication?
yes
id
8c5d5706-5313-4659-b077-33915fe41f18
date added to LUP
2019-01-27 10:44:03
date last changed
2019-05-21 04:17:55
@article{8c5d5706-5313-4659-b077-33915fe41f18,
  abstract     = {Calculating binding free energies with quan-<br/>tum-mechanical (QM) methods is notoriously time-consum-<br/>ing. In this work, we studied whether such calculations can be<br/>accelerated by using nonequilibrium (NE) molecular<br/>dynamics simulations employing Jarzynski’s equality. We<br/>studied the binding of nine cyclic carboxylate ligands to the<br/>octa-acid deep-cavity host from the SAMPL4 challenge with<br/>the reference potential approach. The binding free energies<br/>were first calculated at the molecular mechanics (MM) level<br/>with free energy perturbation using the generalized Amber<br/>force field with restrained electrostatic potential charges for<br/>the host and the ligands. Then the free energy corrections for going from the MM Hamiltonian to a hybrid QM/MM Hamiltonian were estimated by averaging over many short NE molecular dynamics simulations. In the QM/MM calculations, the ligand was described at the semiempirical PM6-DH+ level. We show that this approach yields MM → QM/MM free energy corrections that agree with those from other approaches within statistical uncertainties. The desired precision can be obtained by running a proper number of independent NE simulations. For the systems studied in this work, a total simulation length of 20 ps was appropriate for most of the ligands, and 36−324 simulations were necessary in order to reach a precision of 0.3 kJ/ mol.},
  author       = {Wang, Meiting and Mei, Ye and Ryde, Ulf},
  issn         = {1549-9618},
  language     = {eng},
  month        = {10},
  pages        = {6613--6613},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations},
  url          = {http://dx.doi.org/10.1021/acs.jctc.8b00685},
  volume       = {14},
  year         = {2018},
}