Finally, the BACE(Hunt) target, includes a series of substituted phenyl additions to a spirocyclic core. Here, the grown cyanophenyl group is rotated by approximately 90 • , relative to the crystal structure, which shows the meta-CN group accommodated in the binding pocket (Figure ). An exact match with the crystal structure is also output, but it is predicted to be around 3 kcal/mol higher in energy. Closer examination of the experimental structure reveals a crystal water molecule, close to the binding pocket, that is capable of forming a hydrogen bond with the -CN group, and a further network of water molecules that would be displaced by the conformation shown in Figure (f). Figure investigates the effects of including the hydrogen-bonding water molecule in the receptor structure, and changing the force fields used, but no input settings recover the crystal structure. Accurately including the energetics and effects on binding affinity of displacing water networks in hydrated binding pockets is evidently still a challenge.