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Can MM/GBSA calculations be sped up by system truncation?

Misini Ignjatović, Majda; Mikulskis, Paulius LU ; Söderhjelm, Pär LU and Ryde, Ulf LU (2018) In Journal of Computational Chemistry 39(7). p.361-372
Abstract

We have studied whether calculations of the binding free energy of small ligands to a protein by the MM/GBSA approach (molecular mechanics combined with generalized Born and surface area solvation) can be sped up by including only a restricted number of atoms close to the ligand. If the protein is truncated before the molecular dynamics (MD) simulations, quite large changes are observed for the calculated binding energies, for example, 4 kJ/mol average difference for a radius of 19 Å for the binding of nine phenol derivatives to ferritin. The results are improved if no atoms are fixed in the simulations, with average and maximum errors of 2 and 3 kJ/mol at 19 Å and 3 and 6 kJ/mol at 7 Å. Similar results are obtained for two additional... (More)

We have studied whether calculations of the binding free energy of small ligands to a protein by the MM/GBSA approach (molecular mechanics combined with generalized Born and surface area solvation) can be sped up by including only a restricted number of atoms close to the ligand. If the protein is truncated before the molecular dynamics (MD) simulations, quite large changes are observed for the calculated binding energies, for example, 4 kJ/mol average difference for a radius of 19 Å for the binding of nine phenol derivatives to ferritin. The results are improved if no atoms are fixed in the simulations, with average and maximum errors of 2 and 3 kJ/mol at 19 Å and 3 and 6 kJ/mol at 7 Å. Similar results are obtained for two additional proteins, p38α MAP kinase and factor Xa. On the other hand, if energies are calculated on snapshots that are truncated after the MD simulation, all residues more than 8.5 Å from the ligand can be omitted without changing the energies by more than 1 kJ/mol on average (maximum error 1.4 kJ/mol). At the molecular mechanics level, the gain in computer time for such an approach is small. However, it shows what size of system should be used if the energies instead are calculated with a more demanding method, for example, quantum-mechanics.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
factor Xa, ferritin, ligand-binding affinities, MM/GBSA, p38α MAP kinase, system truncation
in
Journal of Computational Chemistry
volume
39
issue
7
pages
12 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85035062929
ISSN
0192-8651
DOI
10.1002/jcc.25120
language
English
LU publication?
yes
id
dfd63698-d939-4af2-980a-e4831791b444
date added to LUP
2018-02-08 07:41:46
date last changed
2018-02-09 03:00:02
@article{dfd63698-d939-4af2-980a-e4831791b444,
  abstract     = {<p>We have studied whether calculations of the binding free energy of small ligands to a protein by the MM/GBSA approach (molecular mechanics combined with generalized Born and surface area solvation) can be sped up by including only a restricted number of atoms close to the ligand. If the protein is truncated before the molecular dynamics (MD) simulations, quite large changes are observed for the calculated binding energies, for example, 4 kJ/mol average difference for a radius of 19 Å for the binding of nine phenol derivatives to ferritin. The results are improved if no atoms are fixed in the simulations, with average and maximum errors of 2 and 3 kJ/mol at 19 Å and 3 and 6 kJ/mol at 7 Å. Similar results are obtained for two additional proteins, p38α MAP kinase and factor Xa. On the other hand, if energies are calculated on snapshots that are truncated after the MD simulation, all residues more than 8.5 Å from the ligand can be omitted without changing the energies by more than 1 kJ/mol on average (maximum error 1.4 kJ/mol). At the molecular mechanics level, the gain in computer time for such an approach is small. However, it shows what size of system should be used if the energies instead are calculated with a more demanding method, for example, quantum-mechanics.</p>},
  author       = {Misini Ignjatović, Majda and Mikulskis, Paulius and Söderhjelm, Pär and Ryde, Ulf},
  issn         = {0192-8651},
  keyword      = {factor Xa,ferritin,ligand-binding affinities,MM/GBSA,p38α MAP kinase,system truncation},
  language     = {eng},
  month        = {03},
  number       = {7},
  pages        = {361--372},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Computational Chemistry},
  title        = {Can MM/GBSA calculations be sped up by system truncation?},
  url          = {http://dx.doi.org/10.1002/jcc.25120},
  volume       = {39},
  year         = {2018},
}