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Acta Crystallogr B Struct Sci Cryst Eng Mater. 2017 Apr 1;73(Pt 2):188-194. doi: 10.1107/S205252061700138X. Epub 2017 Mar 14.

The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen-bond scoring strategy.

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Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.


The combination of quantum mechanics/molecular mechanics-driven (QM/MM) molecular docking with binding free-energy calculations was successfully used to reproduce the X-ray geometries of protein-ligand complexes with halogen bonding. The procedure involves quantum-polarized ligand docking (QPLD) to obtain the QM-derived ligand atomic charges in the protein environment at the B3PW91/cc-pVTZ level and the MM/GBSA (generalized-Born/surface area) algorithm to calculate the binding free energies of resultant complexes. The performance was validated using a set of 106 X-ray complexes and compared with the Glide and AutoDock VinaXB scoring functions in terms of RMSD and the reconstruction of halogen-bond geometry (distance and σ-hole angle). The results revealed that docking and scoring using the QPLD-GBSA procedure outperformed the remaining scoring functions in the majority of instances. Additionally, a comparison of the orientation of the top ranked binding poses calculated using the fixed atomic charges of ligands obtained from force-field parameterization and by QM calculations in the protein environment provides strong evidence that the use of QM-derived charges is significant.


MM/GBSA free energy calculation; QM/MM docking; halogen bond; scoring function


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