The contact-derived profile in distance space is consistently higher in free energy, highlighting the peril of measuring progress along the wrong reaction coordinate. Rarely sampled regions in space, such as when the quinone headgroup is far away from the membrane surface, will have very high free energies calculated from the joint probability density. Thus the real take-away is not the 20 kcal mol -1 free energy estimate for pulling a sorgoleone molecule out of the membrane, as we believe that the contact number-based value of 13-14 kcal mol -1 from Fig. is likely more accurate, but that desorption processes are likely to be rate limiting given the large free energy change.