| Abstract
| - We implemented a novel approach to score water mediation and displacement in the protein−ligand docking program GOLD. The method allows water molecules to switch on and off andto rotate around their three principal axes. A constant penalty, σp, representing the loss ofrigid-body entropy, is added for water molecules that are switched on, hence rewarding waterdisplacement. We tested the methodology in an extensive validation study. First, σp is optimizedagainst a training set of 58 protein−ligand complexes. For this training set, our algorithmcorrectly predicts water mediation/displacement in ∼92% of the cases. We observed smallimprovements in the quality of the predicted binding modes for water-mediated complexes. Inthe second part of this work, an entirely independent set of 225 complexes is used. For thistest set, our algorithm correctly predicts water mediation/displacement in ∼93% of the cases.Improvements in binding mode quality were observed for individual water-mediated complexes.
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