Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations.
Heimdal, Jimmy LU and Ryde, Ulf LU
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2967122
- author
- Heimdal, Jimmy
LU
and Ryde, Ulf
LU
- organization
- publishing date
- 2012
- 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
- 2023-01-03 22:03:05
@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}},
}