Mycolactone Toxin Membrane Permeation: Atomistic versus Coarse-Grained MARTINI Simulations

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Mycolactone is the primary virulence factor in Buruli ulcer, a skin disease caused by Mycobacterium ulcerans.
• This macrolide toxin disrupts cellular functions, including cell adhesion, immune response, and cell death.
• Developing diagnostics for mycolactone is difficult due to its suspected interaction with lipid structures like cell membranes.

Purpose of the Study:

• To elucidate the interaction mechanisms between mycolactone isomers (A and B) and dipalmitoylphosphatidylcholine (DPPC) membranes.
• To understand how mycolactone permeates lipid bilayers, aiding Buruli ulcer diagnostic development.
• To compare all-atom and coarse-grained simulation methods for studying amphiphile-membrane interactions.

Main Methods:

• All-atom molecular dynamics simulations with transition-tempered metadynamics were used to characterize mycolactone-membrane interactions.
• MARTINI coarse-grained simulations were performed for comparison.
• Free energy calculations and molecular trajectories were analyzed.

Main Results:

• Both mycolactone isomers exhibit a strong preference for associating with DPPC membranes.
• Distinct mechanisms and energetics were observed for the membrane permeation of mycolactone A and B.
• Water molecules play a crucial role in the mycolactone membrane permeation process.
• Coarse-grained simulations accurately predicted membrane association but failed to capture permeation details and the role of water.

Conclusions:

• Mycolactone-membrane interactions are complex, with isomer-specific permeation pathways.
• All-atom simulations provide a more accurate representation of mycolactone's interaction with and permeation through lipid bilayers.
• Understanding these interactions is vital for developing targeted diagnostics and therapeutics for Buruli ulcer.