To investigate whether the Boresch-style restraints were a source for the large dissipation seen in the reverse process (orange work distribution Figure ), we performed calculations applying a lower force constant on the orientational (Boresch-style) restraints (see SI Figure ). The average dissipated work W d , where was the same for both protocols (1.7 kcal/mol in the reverse direction and 0.9 kcal/mol in the forward direction).