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Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations.

Heimdal, Jimmy LU and Ryde, Ulf LU orcid (2012) In Physical chemistry chemical physics : PCCP 14(36). p.12592-12604
Abstract
Lately, there has been great interest in performing free-energy perturbation (FEP) at the combined quantum mechanics and molecular mechanics (QM/MM) level, e.g. for enzyme reactions. Such calculations require extensive sampling of phase space, which typically is prohibitive with density-functional theory or ab initio methods. Therefore, such calculations have mostly been performed with semiempirical QM (SQM) methods, or by using a thermodynamic cycle involving sampling at the MM level and perturbations between the MM and QM/MM levels of theory. However, the latter perturbations typically have convergence problems, unless the QM system is kept fixed during the simulations, because the MM and QM/MM descriptions of the internal degrees of... (More)
Lately, there has been great interest in performing free-energy perturbation (FEP) at the combined quantum mechanics and molecular mechanics (QM/MM) level, e.g. for enzyme reactions. Such calculations require extensive sampling of phase space, which typically is prohibitive with density-functional theory or ab initio methods. Therefore, such calculations have mostly been performed with semiempirical QM (SQM) methods, or by using a thermodynamic cycle involving sampling at the MM level and perturbations between the MM and QM/MM levels of theory. However, the latter perturbations typically have convergence problems, unless the QM system is kept fixed during the simulations, because the MM and QM/MM descriptions of the internal degrees of freedom inside the QM system are too dissimilar. We have studied whether the convergence of the MM → QM/MM perturbation can be improved by using a thoroughly parameterised force field or by using SQM/MM methods. As a test case we use the first half-reaction of haloalkane dehalogenase and the QM calculations are performed with the PBE, B3LYP, and TPSSH density-functional methods. We show that the convergence can be improved with a tailored force field, but only locally around the parameterised state. Simulations based on SQM/MM methods using the MNDO, AM1, PM3, RM1, PDDG-MNDO, and PDDG-PM3 Hamiltonians have slightly better convergence properties, but very long simulations are still needed (∼10 ns) and convergence is obtained only if electrostatic interactions between the QM system and the surroundings are ignored. This casts some doubts on the common practice to base QM/MM FEPs on semiempirical simulations without any reweighting of the trajectories. (Less)
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author
and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Physical chemistry chemical physics : PCCP
volume
14
issue
36
pages
12592 - 12604
publisher
Royal Society of Chemistry
external identifiers
  • wos:000307900800019
  • pmid:22797613
  • scopus:84865471425
  • pmid:22797613
ISSN
1463-9084
DOI
10.1039/c2cp41005b
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)
id
e02d6896-13b2-4e04-b238-4d440836ad18 (old id 2967122)
date added to LUP
2016-04-01 13:16:21
date last changed
2025-10-14 09:43:19
@article{e02d6896-13b2-4e04-b238-4d440836ad18,
  abstract     = {{Lately, there has been great interest in performing free-energy perturbation (FEP) at the combined quantum mechanics and molecular mechanics (QM/MM) level, e.g. for enzyme reactions. Such calculations require extensive sampling of phase space, which typically is prohibitive with density-functional theory or ab initio methods. Therefore, such calculations have mostly been performed with semiempirical QM (SQM) methods, or by using a thermodynamic cycle involving sampling at the MM level and perturbations between the MM and QM/MM levels of theory. However, the latter perturbations typically have convergence problems, unless the QM system is kept fixed during the simulations, because the MM and QM/MM descriptions of the internal degrees of freedom inside the QM system are too dissimilar. We have studied whether the convergence of the MM → QM/MM perturbation can be improved by using a thoroughly parameterised force field or by using SQM/MM methods. As a test case we use the first half-reaction of haloalkane dehalogenase and the QM calculations are performed with the PBE, B3LYP, and TPSSH density-functional methods. We show that the convergence can be improved with a tailored force field, but only locally around the parameterised state. Simulations based on SQM/MM methods using the MNDO, AM1, PM3, RM1, PDDG-MNDO, and PDDG-PM3 Hamiltonians have slightly better convergence properties, but very long simulations are still needed (∼10 ns) and convergence is obtained only if electrostatic interactions between the QM system and the surroundings are ignored. This casts some doubts on the common practice to base QM/MM FEPs on semiempirical simulations without any reweighting of the trajectories.}},
  author       = {{Heimdal, Jimmy and Ryde, Ulf}},
  issn         = {{1463-9084}},
  language     = {{eng}},
  number       = {{36}},
  pages        = {{12592--12604}},
  publisher    = {{Royal Society of Chemistry}},
  series       = {{Physical chemistry chemical physics : PCCP}},
  title        = {{Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations.}},
  url          = {{https://lup.lub.lu.se/search/files/3269621/3412391.pdf}},
  doi          = {{10.1039/c2cp41005b}},
  volume       = {{14}},
  year         = {{2012}},
}