QM-Polarized Ligand Docking

Overview

Accurate treatment of electrostatic charges is crucial to the success of any docking algorithm. Although contemporary force fields are capable of modeling partial atomic charges on ligands with reasonable accuracy, they are generally incapable of considering charge polarization induced by the protein environment. The greater the role charge polarization plays in determining a ligand's bound conformation, the more difficult it will be for MM docking algorithms to perceive the correct binding mode. For research applications that demand the highest level of docking accuracy, Schrödinger introduces QM-Polarized Ligand Docking (QPLD), which uses ab inito charge calculations to overcome this limitation.

QPLD combines the docking power of Glide with the accuracy of QSite, Schrödinger's respected QM/MM software. The QPLD algorithm begins with a Glide docking job that generates several geometrically unique protein-ligand complexes. QSite then performs a single-point energy calculation on each complex, treating the ligand with ab initio methods and deriving partial atomic charges using electrostatic potential fitting. Glide then re-docks the ligand using each of the ligand charge sets calculated by QSite, and the QPLD algorithm returns the most energetically favorable pose. The fully automated algorithm is calibrated to provide useful default settings that can be modified at the user's discretion.

In keeping with Schrödinger's tradition of pairing innovation and practicality, QPLD calculations are effortlessly set up and launched using a single panel within the Maestro interface. Calculations are easily parallelized across multiple processors, and results are automatically incorporated into Maestro for visualization and analysis.

Features

Rigorously tested throughout its development, QPLD has been shown to provide substantial improvements in docking accuracy over pure MM methods. Across a test set of 271 protein-ligand complexes taken from the PDB, QPLD succeeded in docking the ligand with an average RMSD of less than one angstrom (below).

In validation experiments comparing QPLD against pure force field methods, ligands were docked into their native crystal structure using both QPLD and Glide's standard precision (SP) mode. Across the 271 complex test set, QPLD offered superior docking accuracy: the average RMSD of QPLD-docked ligands was nearly half that obtained by Glide SP. The above histogram illustrates the distribution of ligand RMSDs obtained by QPLD and force field docking. QPLD returns extremely high accuracy poses (RMSD below 0.5 Å) for over 120 ligands in the test set, while reducing the overall number of low accuracy poses (RMSD above 3.0 Å) to less than 20.

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Citations and Acknowledgements

Schrödinger Release 2021-4: QM-Polarized Ligand Docking protocol; Glide, Schrödinger, LLC, New York, NY, 2021; Jaguar, Schrödinger, LLC, New York, NY, 2021; QSite, Schrödinger, LLC, New York, NY, 2021.

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