A molecular dynamics study of PIM2 lipid bilayer membranes.

Developing simplified yet representative models of the complex Mycobacterium tuberculosis inner membrane is crucial for advancing Molecular Dynamics of this pathogen. Phosphatidyl-myo-inositol dimannosides (PIM2), one of the most abundant lipids in this membrane, provides an ideal basis for such a model. In this study, we proposed a minimal, single-component atomistic PIM2 bilayer for use in M. tuberculosis research. We validate the model by assessing its ability to reproduce distinct temperature-dependent ordering regimes, with a more ordered, gel-like behavior at 310 K and increased fluidity at 363.15 K, its capacity for spontaneous self-assembly, and its interaction with the native transmembrane efflux pump, Tap (Rv1258c). Our simulations confirm that the model exhibits the correct phase behavior at experimental temperatures and readily self-assembles into an extended lamellar bilayer-like structure. Importantly, the PIM2 membrane provides a significantly more stable environment for the embedded Tap protein compared to a standard dipalmitoylphosphatidylcholine (DPPC) bilayer. These findings confirm the PIM2 bilayer as a robust and promising model. It is particularly well suited for investigating the protein-lipid interactions central to multidrug resistance in M. tuberculosis and for exploring phenomena such as the bacterial immunological thermostat.