Mycobacterium tuberculosis (Mtb), the gram-positive bacterium responsible for tuberculosis, resists environmental pressure and antibiotic attack with a uniquely complex cell wall. The mycobacterial cell wall consists of three layers: an asymmetric outer membrane, periplasmic arabinogalactan and peptidoglycan layers that are connected to the outer membrane, and an asymmetric inner membrane. Although it is difficult to study in a traditional lab setting, this complex membrane can be efficiently studied using molecular modeling and simulation. The arabinogalactan layer is an intriguing drug target, because it links the outer membrane to the peptidoglycan layer, providing structural integrity, and binds to the host protein galectin-9, acting as a virulence factor. However, questions still remain about how the arabinogalactan layer reorganizes between disease states. In our previous study, an all-atom outer membrane was modeled and simulated, revealing heterogeneous fluidity across the asymmetric membrane. To extend this work, we have simulated all-atom models of the outer membrane connected to arabinogalactans. By varying the number of arabinogalactan-mycolate connections in the lower leaflet, the number of arabinogalactans in the system, and the initial extension of the galactan chains, we have investigated how subtle changes in the arabinogalactan organization can affect physical properties of the outer membrane. This work represents a major step toward modelling of the full cell wall of Mtb and suggests a link between arabinogalactan organization and outer membrane permeability.
Brown et al. (Sun,) studied this question.