From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of the Mycobacterial Plasma Membrane

Mycobacterium tuberculosis ( Mtb ) is the causative agent of tuberculosis, a disease that claims ~1.5 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. There is much to be understood about the Mtb cell envelope, a complicated barrier that antibiotics need to negotiate to enter the cell. Within this envelope, the plasma membrane is the ultimate obstacle and is proposed to be comprised of over 50% mannosylated phosphatidylinositol lipids (phosphatidyl- myo inositol mannosides, PIMs), whose role in the membrane structure remains elusive. Here we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to drive biophysical properties of the Mycobacterial plasma membrane. To validate the model, we tested known anti-tubercular drugs and replicated previous experimental results. Our results shed new light into the organization of the Mycobacterial plasma membrane and provides a working model of this complex membrane to use for in silico studies. This opens the door for new methods to probe potential antibiotic targets and further understand membrane protein function. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * AT : Atomistic ATP : Adenosine triphosphate BDQ : Bedaquiline CL : Cardiolipin CG : Coarse grained ISZ : Isoniazid LAM : Lipoarabinomannan LM : Lipomannan MD : Molecular dynamics Mtb : Mycobacterium tuberculosis PC : Phosphatidylcholine PE : Phosphatidylethanolamine PG : Phosphatidylglycerol PI : Phosphatidylinositol PIMs : Mannosylated phosphatidylinositol lipids PIPs : Phosphatidylinositol phosphates PME : Particle mesh Ewald PMF : Potential of mean force TB : Tuberculosis TMM : Trehalose monomycolate [1]: pending:yes