A dramatically greater allocation of sampling time for the bound vanish stage of the first protocol (458 ns) was observed compared to the second protocol (16 ns). This suggests that using different starting velocities alone may be insufficient to sample diverse local minima in the initial stages of the adaptive runs. However, the shared starting structure protocol produced an overall result (-5.26 ± 0.35 kcal mol -1 ) in better agreement with experiment (-5.19 ± 0.16 kcal mol -1 ) than the diverse starting structure protocol (-4.33 ± 0.67 kcal mol -1 ), perhaps suggesting that entry of any waters to this binding site is an artefact of simulation.