The results shown for -∆G o Release were calculated by numerical integration of Equation . While use of the Boresch analytical correction introduces large errors in certain regimes (force constants very weak, r very short, θ A or θ B close to 0 or π rad), only small deviations between the analytical and numerical corrections, no greater than 0.04 kcal mol -1 , were found for any of the Boresch restraints. This is in accordance with previous studies. The average of repeat runs for B1 -3 and B1-poseB generally showed good convergence as assessed by lack of drift with increasing sampling time (Section S8). However, there were substantial differences between replicate runs, most notably during the vanishing stage, which generally contributed the greatest uncertainty to ∆G o Bound . In all cases, this uncertainty could be traced back to a few windows around λ = 0.4 (Figure ).