A QM/MM study of the binding of RAPTA ligands to cathepsin B
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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-[126.96.36.199] 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.
KeywordsQM/MM Ligand-binding affinities Ruthenium Anticancer drugs Cathepsin B Continuum solvation QM/MM-PBSA
We thank Dr. Alessandro Marrone who provided us the initial docked structures. This investigation has been supported by grants from the Swedish research council (project 2010-5025) and from the Research school in pharmaceutical science. It has also been supported by computer resources of Lunarc at Lund University and HPC2N at Umeå University.
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