bubble-ligand sits on top of the normal ligand but interacts only with the water molecules (Figure ). The three buried water molecules were chosen not to interact with this bubbleligand and were restrained with position restraints. This bubble-ligand reduces the dissipation in NEQ and overcomes sampling problems in the EQ approach. Even though the water problem should be accounted for in the NEQ theorem, we found that large dissipation required long transition times or a huge number of switching transitions which became computationally expensive. Our hope was that this approach might isolate some water sampling problems. However, we found that when the ligand was decoupled, the bubble-ligand created a vacuum in the binding site which created its own problems. Side chains of a loop close to the binding site moved in to this vacuum making it necessary to restrain their backbone atoms as well.