Placement of Water Molecules in Protein Structures: From Large-Scale Evaluations to Single-Case Examples

Water
molecules are of great importance for the correct representation
of ligand binding interactions. Throughout the last years, water molecules
and their integration into drug design strategies have received increasing
attention. Nowadays a variety of tools are available to place and
score water molecules. However, the most frequently applied software
solutions require substantial computational resources. In addition,
none of the existing methods has been rigorously evaluated on the
basis of a large number of diverse protein complexes. Therefore, we
present a novel method for placing water molecules, called WarPP,
based on interaction geometries previously derived from protein crystal
structures. Using a large, previously compiled, high-quality validation
set of almost 1500 protein–ligand complexes containing almost
20 000 crystallographically observed water molecules in their
active sites, we validated our placement strategy. We correctly placed
80% of the water molecules within 1.0 Å of a crystallographically
observed one.