The heterogeneity of membranes is increasingly recognized as an influential factor in biomolecular processes. Here we describe how mycolactone, an amphipathic toxin that causes the neglected tropical skin disease Buruli ulcer, preferentially associates with and localizes in membranes of various compositions. Using molecular simulations with enhanced free energy sampling methods we compare the toxin’s interactions with the plasma membrane versus endoplasmic reticulum (ER) membrane, with saturated versus unsaturated lipid tails, and with curved versus flat membranes. We find preferential interactions with the more fluid ER membrane facilitated by interactions with water molecules and linactant-like properties that would influence cellular localization. The toxin’s influence on membrane properties will be discussed and an isomeric specificity demonstrated, suggesting that membrane interactions may contribute to the toxicity of one isomer over the other. This work calls into question the role that membrane heterogeneity plays in the localization of amphiphilic molecules and highlights how membranes can facilitate toxin pathogenicity while complicating the detection of amphiphilic biomarkers.

Role of membranes in the localization and pathogenicity of amphipathic molecules

ACS Spring 2022

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