A QM/MM study of the binding of RAPTA ligands to cathepsin B
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/2252728
- author
- Ciancetta, Antonella ; Genheden, Samuel LU and Ryde, Ulf LU
- organization
- publishing date
- 2011
- 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
- Springer
- external identifiers
-
- wos:000297133100004
- scopus:80055066394
- pmid:21701919
- ISSN
- 1573-4951
- DOI
- 10.1007/s10822-011-9448-7
- 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
- 182cd764-6fae-4c85-b5c9-7f171641a26c (old id 2252728)
- date added to LUP
- 2016-04-01 13:06:28
- date last changed
- 2023-04-06 00:22:56
@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}}, keywords = {{QM/MM; Ligand-binding affinities; Ruthenium; Anticancer drugs; Cathepsin B; Continuum solvation; QM/MM-PBSA}}, language = {{eng}}, number = {{8}}, pages = {{729--742}}, publisher = {{Springer}}, series = {{Journal of Computer-Aided Molecular Design}}, title = {{A QM/MM study of the binding of RAPTA ligands to cathepsin B}}, url = {{https://lup.lub.lu.se/search/files/3163780/3412395.pdf}}, doi = {{10.1007/s10822-011-9448-7}}, volume = {{25}}, year = {{2011}}, }