Abstract
Water molecules play an important role in modeling protein-ligand interactions. However, traditional molecular docking methods often ignore the impact of the water molecules by removing them without any analysis or keeping them as a static part of the proteins or the ligands. Hence, the accuracy of the docking simulations will inevitably be damaged. Here, we introduce a multi-body docking program which incorporates the fixed or the variable number of the key water molecules in protein-ligand docking simulations. The program employed NSGA II, a multi-objective optimization algorithm, to identify the binding poses of the ligand and the key water molecules for a protein. To this end, a force-field-based hydration-specific scoring function was designed to favor estimate the binding affinity considering the key water molecules. The program was evaluated in aspects of the docking accuracy, cross-docking accuracy, and screening efficiency. When the numbers of the key water molecules were treated as fixed-length optimization variables, the docking accuracy of the multi-body docking program achieved a success rate of 80.58% for the best RMSD values for the recruit of the ligands smaller than 2.0 Å. The cross-docking accuracy was investigated on the presence and absence of the key water molecules by four protein targets. The screening efficiency was assessed against those protein targets. Results indicated that the proposed multi-body docking program was with good performance compared with the other programs. On the other side, when the numbers of the key water molecules were treated as variable-length optimization variables, the program obtained comparative performance under the same three evaluation criterions. These results indicated that the multi-body docking with the variable numbers of the water molecules was also efficient. Above all, the multi-body docking program developed in this study was capable of dealing with the problem of the water molecules that explicitly participating in protein-ligand binding.
Highlights
Protein-ligand docking simulation plays a key role in the general field of molecular docking, because of the effect of the discovery of lead compounds and the analysis of structure-activity relationships
The performance of the multi-body docking program was evaluated in aspects of the docking accuracy, cross-docking accuracy, and screening efficiency
The success rates of 56.00%, 36.00%, 68.00%, and 40.00% were achieved in the cross-docking simulations on the presence of the water molecules of purine nucleoside phosphorylase (PNP), cyclooxygenase 1 (COX-1), HIV reverse transcriptase (HIVRT), and ER agonist, respectively, which were higher than the rates of 28.00%, 32.00%, 48.00%, and 36.00% in the docking simulation without the water molecules
Summary
Protein-ligand docking simulation plays a key role in the general field of molecular docking, because of the effect of the discovery of lead compounds and the analysis of structure-activity relationships. Molecules 2018, 23, 2321 prediction of the binding affinity [2], one remaining challenge in molecular docking is positioning the interface water molecules and evaluating the energetic contribution implied by the presence or displacement of the water molecules in the binding sites of crystal structures. The cross-docking simulations had been performed on a number of ligand-protein complexes for various proteins whose crystal structures contain water molecules in their binding sites. One simple way is to include the water molecules as a static part of the protein structures in the docking simulations This strategy is feasible only if the number of the key water molecules is few. Motivated by the above discussions, in this study, a multi-body docking program which incorporates the key water molecules in protein-ligand docking simulations was introduced. The performance of the multi-body docking program was evaluated in aspects of the docking accuracy, cross-docking accuracy, and screening efficiency
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