From dioxin to dioxin congeners: understanding the differences in hydrophobic aggregation in water and absorption into lipid membranes by means of atomistic simulations

Translocation of small molecules through a cell membrane barrier is a fundamental step to explain the response of cells to foreign molecules. Investigating the mechanisms through which this complex process takes place is especially important in the study of the adverse effects of toxicants. In this work, we start from the results of a previous simulation study of the mechanism of dioxin (2,3,7, 8-tetrachlorodibenzo-p-dioxin) absorption into a model membrane, and extend it to four structural congeners of dioxin. The new molecules have been chosen taking into consideration the structural features that characterize dioxin: aromaticity, planarity, the presence of chlorine and oxygen atoms, and hydrophobicity. Our results for the absorption mechanism confirm our expectations based on the chemical structures, but also reveal some interesting differences in single-molecules and especially in cooperative actions underlying cluster absorption. The analysis of key parameters, such as free energies of transfer and translocation times, supports the idea that dioxin, more than its congeners investigated here, likely accumulates in cell membranes.