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3927821 - Buruli ulcer disease: Unveiling toxin pathogenicity through enhanced sampling simulations


‐ Aug 17, 2023 11:20am

The neglected skin tropical Buruli ulcer disease is characterized by large necrotic lesions that can cause permanent disfigurement if left untreated. It is caused by a single molecule: the mycolactone toxin. Due to its amphiphilic nature, the toxin hides from traditional diagnostic detection and the host immune system by associating with lipophilic carriers, like cellular membranes. Mycolactone invades and kills host cells passing through the plasma membrane (PM) to induce a range of effects, including uncontrolled actin branching and blockage of the sec61 translocon in the endoplasmic reticulum (ER) membrane. It is likely that preferential interactions with lipophilic carriers play a key role in the toxin’s distribution in the host, which, if understood, could provide insights to aid in the development of needed diagnostics for Buruli ulcer disease. In this work, we used molecular dynamics simulations combined with enhanced free energy sampling to characterize the toxin’s association with and permeation through the membranes. We find that increased order in the PM leads to a different permeation mechanism and less favorable association compared to that in the ER. Increased hydration, membrane deformation, and preferential interactions with unsaturated lipid tails stabilize the toxin in the ER membrane, while disruption of lipid packing is a destabilizing force in the PM. These results potentially explain how the toxin preferentially targets the ER within two minutes of host cell exposure.
Figure shows a mycolactone toxin inside a membrane bilayer, with its hydrophilic chains interacting with lipid headgroups. On the side, a graph shows that the energy is lower is ER membrane than PM.

Figure shows a mycolactone toxin inside a membrane bilayer, with its hydrophilic chains interacting with lipid headgroups. On the side, a graph shows that the energy is lower is ER membrane than PM.