Water molecules play an important role in protein-ligand recognition. However, incorporating explicit waters during docking is challenging in both the sampling and scoring aspects. We explored a method to switch ordered water molecules �on� (retained) and �off� (displaced) during docking screens. This method assumes additivity and scales linearly with the number of waters sampled despite the exponential growth in configurations. We tested this approach for ligand enrichment in screens of a large compound database against 24 DUD targets, exploring up to 8 waters in 256 configurations. Compared to calculations where the water positions were not sampled, enrichment factors increase substantially for 12 of the targets and are largely unaffected for most others. However, in our previous study, the positions of the water molecules were obtained from the x-ray structures, and all waters were treated as equally displaceable without the consideration of the differential energy of water binding. Our recent work in improving the treatment of waters during docking and scoring will be presented.

Modeling explicit waters in docking and scoring

240th National Meeting (2010)

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