For the Boresch restraints, ∆G o Release was calculated by numerical integration of Equation . This was used in preference to the analytical correction to avoid potential errors introduced by the approximations required to derive Equation . For multiple distance restraints, numerical integration of Equation 10 was performed using the "standardstatecorrection" utility available within Sire, using all frames of the trajectory, a buffer of 5 Å, a translational volume element of 0.25 Å, and 30 orientations per [0, 2π] Euler angle interval.