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Relative Ligand-Binding Free Energies Calculated from Multiple Short QM/MM MD Simulations

Ryde, Ulf LU orcid ; Olsson, Martin LU and Steinmann, Casper (2018) In Journal of Chemical Theory and Computation 14. p.3228-3228
Abstract
We have devised a new efficient approach to
compute combined quantum mechanical (QM) and molecular
mechanical (MM, i.e. QM/MM) ligand-binding relative free
energies. Our method employs the reference-potential
approach with free-energy perturbation both at the MM
level (between the two ligands) and from MM to QM/MM
(for each ligand). To ensure that converged results are
obtained for the MM → QM/MM perturbations, explicit
QM/MM molecular dynamics (MD) simulations are
performed with two intermediate mixed states. To speed up the calculations, we utilize the fact that the phase space can be extensively sampled at the MM level. Therefore, we run many short QM/MM MD simulations started from snapshots of the MM... (More)
We have devised a new efficient approach to
compute combined quantum mechanical (QM) and molecular
mechanical (MM, i.e. QM/MM) ligand-binding relative free
energies. Our method employs the reference-potential
approach with free-energy perturbation both at the MM
level (between the two ligands) and from MM to QM/MM
(for each ligand). To ensure that converged results are
obtained for the MM → QM/MM perturbations, explicit
QM/MM molecular dynamics (MD) simulations are
performed with two intermediate mixed states. To speed up the calculations, we utilize the fact that the phase space can be extensively sampled at the MM level. Therefore, we run many short QM/MM MD simulations started from snapshots of the MM simulations, instead of a single long simulation. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep cavitand. Only the ligand is in the QM system, treated with the semiempirical PM6-DH+ method. We show that for eight of the ligands, we obtain well converged results with short MD simulations (1−15 ps). However, in one case, the convergence is slower (∼50 ps) owing to a mismatch between the conformational preferences of the MM and QM/MM potentials. We test the effect of initial minimization, the need of equilibration, and how many independent simulations are needed to reach a certain precision. The results show that the present approach is about four times faster than using standard MM → QM/MM free-energy perturbations with the same accuracy and precision. (Less)
Please use this url to cite or link to this publication:
author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
14
pages
3237 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:29768915
  • scopus:85047439320
ISSN
1549-9618
DOI
10.1021/acs.jctc.8b00081
language
English
LU publication?
yes
id
e983bc04-c5ad-49bf-ba8e-d054ed1ae8ab
date added to LUP
2019-01-27 11:03:23
date last changed
2021-10-06 03:57:58
@article{e983bc04-c5ad-49bf-ba8e-d054ed1ae8ab,
  abstract     = {We have devised a new efficient approach to<br/>compute combined quantum mechanical (QM) and molecular<br/>mechanical (MM, i.e. QM/MM) ligand-binding relative free<br/>energies. Our method employs the reference-potential<br/>approach with free-energy perturbation both at the MM<br/>level (between the two ligands) and from MM to QM/MM<br/>(for each ligand). To ensure that converged results are<br/>obtained for the MM → QM/MM perturbations, explicit<br/>QM/MM molecular dynamics (MD) simulations are<br/>performed with two intermediate mixed states. To speed up the calculations, we utilize the fact that the phase space can be extensively sampled at the MM level. Therefore, we run many short QM/MM MD simulations started from snapshots of the MM simulations, instead of a single long simulation. As a test case, we study the binding of nine cyclic carboxylate ligands to the octa-acid deep cavitand. Only the ligand is in the QM system, treated with the semiempirical PM6-DH+ method. We show that for eight of the ligands, we obtain well converged results with short MD simulations (1−15 ps). However, in one case, the convergence is slower (∼50 ps) owing to a mismatch between the conformational preferences of the MM and QM/MM potentials. We test the effect of initial minimization, the need of equilibration, and how many independent simulations are needed to reach a certain precision. The results show that the present approach is about four times faster than using standard MM → QM/MM free-energy perturbations with the same accuracy and precision.},
  author       = {Ryde, Ulf and Olsson, Martin and Steinmann, Casper},
  issn         = {1549-9618},
  language     = {eng},
  month        = {05},
  pages        = {3228--3228},
  publisher    = {The American Chemical Society (ACS)},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Relative Ligand-Binding Free Energies Calculated from Multiple Short QM/MM MD Simulations},
  url          = {https://lup.lub.lu.se/search/files/57285565/237_qmmmfep_casper.pdf},
  doi          = {10.1021/acs.jctc.8b00081},
  volume       = {14},
  year         = {2018},
}