title: The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen-bond scoring strategy.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Krakow, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Kurczab
keywords: MM/GBSA free energy calculation; QM/MM docking; halogen bond; scoring function