Search for Potential Water Molecules Bridging between Protein and Ligand

The design of an extension to the HINT (Hydropathic INTeractions) program for locating and automatically placing in relevant orientations bridging water molecules is described in detail. This application is used to analyze the structures of HIV-1 protease-inhibitor complexes for five key bridging water molecules. The tool locates the water molecules with an overall accuracy of 1.28 ± 0.55 Å, and orients them (relative to potentially erroneous molecular mechanics optimized water molecules) to 41 ± 23 degrees. This automated placement is in contrast to other programs that calculate 3D contour maps of energetically-likely binding locations for water molecules, which must be followed by manual placement and energy minimization of these water positions and orientations to create the model. Also, the new object-oriented toolkit design for the HINT progra