On-the-Fly QM/MM Docking with Attracting Cavities.

We developed a hybrid quantum mechanical/molecular mechanical (QM/MM) on-the-fly docking algorithm to address the challenges of treating polarization and selected metal interactions in docking. The algorithm is based on our classical docking algorithm Attracting Cavities and relies on the semiempirical self-consistent charge density functional tight-binding (SCC-DFTB) method and the CHARMM force field. We benchmarked the performance of this approach on three very diverse data sets: (1) the Astex Diverse set of 85 common noncovalent drug/target complexes formed both by hydrophobic and electrostatic interactions; (2) a zinc metalloprotein data set of 281 complexes, where polarization is strong and ligand/protein interactions are dominated by electrostatic interactions; and (3) a heme protein data set of 72 complexes, where ligand/protein interactions are dominated by covalent ligand/iron binding. Redocking performance of the on-the-fly QM/MM docking algorithm was compared to the performance of classical Attracting Cavities, AutoDock, AutoDock Vina, and GOLD. The results demonstrate that the QM/MM code preserves the high accuracy of most classical scores on the Astex Diverse set, while it yields significant improvements on both sets of metalloproteins at moderate computational cost.