From our analysis of leaflet exchange REUS, sorgoleone is the product that diffuses between membrane leaflets most readily. However, the energy barrier for crossing the membrane to an extracellular aqueous environment seems to be more than 10 kcal mol -1 . This high barrier would make it difficult for sorgoleone molecules diffuse out into the extracellular aqueous environment. Upon looking at the unbiased simulation we observed that sorgoleone forms an aggregated mass to insert into the membrane, and that perhaps sorgoleone spontaneously desorbs from the membrane to join the larger aggregate, or at least would do so far more favorably than directly to aqueous solution.