The second and third Yank simulations each used restraints to restrict the toluene ligand to a single binding mode. The restraints used were a set of one bond, two angle, and three dihedral restraints. The sping constant for the bond restraint was set at 10 kcals/(mol*Å 2 ) while the angle and dihedral restraints were set at 10 kcals/(mol*radians 2 ). These restraints were constant throughout the windows.