Development of force field parameters for the atomic simulation of Mycobacterial membranes

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global leading cause of death from a single infectious agent. The unique cell envelope of Mtb, rich in complex lipids, is critical for its pathogenicity, host interaction, and antibiotic tolerance. Understanding the biophysical properties of these complex lipids is crucial but experimentally challenging. Molecular Dynamics (MD) simulations offer atomic-level insights, but the accuracy is hindered by the lack of dedicated force fields. Here, we developed BLipidFF (Bacteria Lipid Force Fields), a specialized all-atom force field for many key bacteria lipids derived from rigorous quantum mechanics-based parameterization. BLipidFF was validated on four representative Mtb outer membrane lipids: phthiocerol dimycocerosate (PDIM), α-mycolic acid (α-MA), trehalose dimycolate (TDM), and sulfoglycolipid-1 (SL-1). MD simulations results revealed that BLipidFF captured many important membrane properties which are poorly described by general force fields, including the rigidity and diffusion rate of α-MA bilayers. The MD simulation predictions based on BLipidFF are well consistent with the biophysical experiment observations. This study not only provides a validated force field for Mtb membrane lipids but also establishes a standardized framework for parameterizing bacterial membrane components, which will greatly improve the studies of bacterial pathogenicity and host-pathogen interactions.