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A QM/MM study of the binding of RAPTA ligands to cathepsin B

Ciancetta, Antonella; Genheden, Samuel LU and Ryde, Ulf LU (2011) In Journal of Computer-Aided Molecular Design 25(8). p.729-742
Abstract
We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson-Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r(2)) of 0.35-0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r(2) = 0.59) when the protein was fixed to the... (More)
We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson-Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r(2)) of 0.35-0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r(2) = 0.59) when the protein was fixed to the crystal structure, but more reasonable ligand structures and absolute binding energies were obtained if the protein was allowed to relax, indicating that the ligands are strained when the protein is kept fixed. In addition, the best correlation (r(2) = 0.80) was obtained when only the QM energies were used, which suggests that the MM and continuum solvation energies are not accurate enough to predict the binding of a charged metal complex to a charged protein. Taking into account the protein flexibility by means of MD simulations slightly improves the correlation (r(2) = 0.91), but the absolute energies are still too large and the results are sensitive to the details in the calculations, illustrating that it is hard to obtain stable predictions when full flexible protein is included in the calculations. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
QM/MM, Ligand-binding affinities, Ruthenium, Anticancer drugs, Cathepsin B, Continuum solvation, QM/MM-PBSA
in
Journal of Computer-Aided Molecular Design
volume
25
issue
8
pages
729 - 742
publisher
Kluwer
external identifiers
  • wos:000297133100004
  • scopus:80055066394
ISSN
1573-4951
DOI
10.1007/s10822-011-9448-7
language
English
LU publication?
yes
id
182cd764-6fae-4c85-b5c9-7f171641a26c (old id 2252728)
date added to LUP
2011-12-22 10:00:58
date last changed
2017-09-24 03:52:13
@article{182cd764-6fae-4c85-b5c9-7f171641a26c,
  abstract     = {We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson-Boltzmann solvent-accessible surface area solvation) has been used to estimate binding affinities. The QM calculations reproduce the antitumour activities of the complexes with a correlation coefficient (r(2)) of 0.35-0.86 after a conformational search. The QM/MM-PBSA method gave a better correlation (r(2) = 0.59) when the protein was fixed to the crystal structure, but more reasonable ligand structures and absolute binding energies were obtained if the protein was allowed to relax, indicating that the ligands are strained when the protein is kept fixed. In addition, the best correlation (r(2) = 0.80) was obtained when only the QM energies were used, which suggests that the MM and continuum solvation energies are not accurate enough to predict the binding of a charged metal complex to a charged protein. Taking into account the protein flexibility by means of MD simulations slightly improves the correlation (r(2) = 0.91), but the absolute energies are still too large and the results are sensitive to the details in the calculations, illustrating that it is hard to obtain stable predictions when full flexible protein is included in the calculations.},
  author       = {Ciancetta, Antonella and Genheden, Samuel and Ryde, Ulf},
  issn         = {1573-4951},
  keyword      = {QM/MM,Ligand-binding affinities,Ruthenium,Anticancer drugs,Cathepsin B,Continuum solvation,QM/MM-PBSA},
  language     = {eng},
  number       = {8},
  pages        = {729--742},
  publisher    = {Kluwer},
  series       = {Journal of Computer-Aided Molecular Design},
  title        = {A QM/MM study of the binding of RAPTA ligands to cathepsin B},
  url          = {http://dx.doi.org/10.1007/s10822-011-9448-7},
  volume       = {25},
  year         = {2011},
}