To test whether the adaptive scheme produced benefits in a favourable case, we performed adaptive and non-adaptive runs for the free vanish stage of MDM2-PIP2. This was selected because it had the most favourable SEM-based improvement factor of any stage (0.37 ± 0.13, Figure ), indicating a sampling issue localised to a few windows. To isolate the effect of the algorithm, the adaptive and non-adaptive runs used the same λ-schedule (an optimised schedule with speed 1.0 kcal mol -1 ). To provide improved statistics, 20 replicates were used for each protocol. A runtime constant of 1×10 -10 kcal 2 mol -2 ns -1 was used for the adaptive runs and the non-adaptive data were truncated slightly above 2 ns per simulation per window to give an equal total computational cost.