AutoDock-GIST: Incorporating Thermodynamics of Active-Site Water into Scoring Function for Accurate Protein-Ligand Docking
By Shota Uehara, Shigenori Tanaka. 2016
45 citations recorded by the source corpus.
Water plays a significant role in the binding process between protein and ligand. However, the thermodynamics of water molecules are often underestimated, or even ignored, in protein-ligand docking. Usually, the free energies of active-site water molecules are substantially different from those of waters in the bulk region. The binding of a ligand to a protein causes a displacement of these waters from an active site to bulk, and this displacement process substantially contributes to the free energy change of protein-ligand binding. The free energy of active-site water molecules can be calculated by grid inhomogeneous solvation theory (GIST), using molecular dynamics (MD) and the trajectory of a target protein and water molecules. Here, we show a case study of the combination of GIST and a docking program and discuss the effectiveness of the displacing gain of unfavorable water in protein-ligand docking. We combined the GIST-based desolvation function with the scoring function of AutoDock4, which is called AutoDock-GIST. The proposed scoring function was assessed employing 51 ligands of coagulation factor Xa (FXa), and results showed that both scoring accuracy and docking success rate were improved. We also evaluated virtual screening performance of AutoDock-GIST using FXa ligands in the directory of useful decoys-enhanced (DUD-E), thus finding that the displacing gain of unfavorable water is effective for a successful docking campaign.
Subfields: Computational Theory and Mathematics, Molecular Biology
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Citations in the corpus
- AutoDock Vina 1.2.0: new docking methods, expanded force field, and Python bindings (2021, methodology): “The availability to accessible grid map files generated by AutoGrid provided the foundations for a number of specialized methods, such as the zinc-coordination potentials in the AutoDock4 Zn force field 13 , biasing docking using information from molecular dynamics simulations in AutoDock-Bias 21 , an”