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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.

Supporting information

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Portable Document Format (PDF) file https://doi.org/10.1107/S205252061700138X/xm5003sup1.pdf
Supporting figures and tables

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Text file https://doi.org/10.1107/S205252061700138X/xm5003sup2.txt
List of PDB ID codes of halogenated ligand-protein complexes used in the analysis

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Text file https://doi.org/10.1107/S205252061700138X/xm5003sup3.txt
List of XB acceptors

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Text file https://doi.org/10.1107/S205252061700138X/xm5003sup4.txt
Target distribution data obtained from PDB files

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Text file https://doi.org/10.1107/S205252061700138X/xm5003sup5.txt
RMSD values for performed tests


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