Prediction of Water Distributions and Displacement at Protein-Ligand Interfaces

The retention and displacement of water molecules duringformation of ligand-protein interfaces play a major role in determiningligand binding. Understanding these effects requires a method for positioningof water molecules in the bound and unbound proteins and for defining waterdisplacement upon ligand binding. We describe an algorithm for waterplacement and a calculation of ligand-driven water displacement in >9000protein-ligand complexes. The algorithm predicts approximately 38% ofexperimental water positions within 1.0 A and about 83% within 1.5 A. Wefurther show that the predicted water molecules can complete water networksnot detected in crystallographic structures of the protein-ligand complexes.The algorithm was also applied to solvation of the corresponding unboundproteins, and this allowed calculation of water displacement upon ligand binding based on differences in the water network betweenthe bound and unbound structures. We illustrate use of this approach through comparison of water displacement by structurallyrelated ligands at the same binding site. This method for evaluation of water displacement upon ligand binding may be of value forprediction of the effects of ligand modification in drug design