Lipids or compounds with long lipophilic tails have heterogeneous tail configurations. A given molecule with long acyl tail may have multiple conformations that resolve to the same center of mass (Fig. ). This potential to map distinct states to equivalent values for a specific collective variable is a well-known issue in the enhanced sampling literature, convolute the interpretation for the center of mass relative to the membrane center for the compounds from Figure . As detailed in the methods, our approach to compute the permeability and partitioning behavior for the selected compounds is to split apart the leaflet exchange or membrane crossing step apart from the adsorption and desorption steps, calculating the free energy and diffusivity needed to determine permeability (Fig. ) in two parts and then merging these elements together to obtain a permeability estimate for sorgoleone and the other related compounds.