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bioRxiv · 10.1101/2022.06.29.498153

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

Brown, C. M.·Corey, R. A.·Gao, Y.·Choi, Y. K.·Gilleron, M.·Destainville, N.·Fullam, E.·Im, W.·Stansfeld, P. J.·Chavent, M.
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Abstract

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-myoinositol 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. O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/498153v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@102b357org.highwire.dtl.DTLVardef@4c30f8org.highwire.dtl.DTLVardef@22f32aorg.highwire.dtl.DTLVardef@8a6f65_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Brown, C. M., Corey, R. A., Gao, Y., Choi, Y. K., Gilleron, M., Destainville, N., Fullam, E., Im, W., Stansfeld, P. J., Chavent, M.. 2022-06-30. From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of the Mycobacterial Plasma Membrane. https://doi.org/10.1101/2022.06.29.498153

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