Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8c5d5706-5313-4659-b077-33915fe41f18
- author
- Wang, Meiting ; Mei, Ye and Ryde, Ulf LU
- organization
- publishing date
- 2018-10-26
- 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 (ACS)
- external identifiers
-
- pmid:30362750
- 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
- 2023-04-09 03:21:52
@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 (ACS)}}, series = {{Journal of Chemical Theory and Computation}}, title = {{Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations}}, url = {{https://lup.lub.lu.se/search/files/57285357/244_jarzynski.pdf}}, doi = {{10.1021/acs.jctc.8b00685}}, volume = {{14}}, year = {{2018}}, }