Abstract
One quarter of the world's population are infected by Mycobacterium tuberculosis (Mtb), which is a leading death-causing bacterial pathogen. Recent evidence has demonstrated that two virulence factors, ESAT-6 and CFP-10, play crucial roles in Mtb's cytosolic translocation. Many efforts have been made to study the ESAT-6 and CFP-10 proteins. Some studies have shown that ESAT-6 has an essential role in rupturing phagosome. However, the mechanisms of how ESAT-6 interacts with the membrane have not yet been fully understood. Recent studies indicate that the ESAT-6 disassociates with CFP-10 upon their interaction with phagosome membrane, forming a membrane-spanning pore. Based on these observations, as well as the available structure of ESAT-6, ESAT-6 is hypothesized to form an oligomer for membrane insertion as well as rupturing. Such an ESAT-6 oligomer may play a significant role in the tuberculosis infection. Therefore, deeper understanding of the oligomerization of ESAT-6 will establish new directions for tuberculosis treatment. However, the structure of the oligomer of ESAT-6 is not known. Here, we proposed a comprehensive approach to model the complex structures of ESAT-6 oligomer inside a membrane. Several computational tools, including MD simulation, symmetrical docking, MM/PBSA, are used to obtain and characterize such a complex structure. Results from our studies lead to a well-supported hypothesis of the ESAT-6 oligomerization as well as the identification of essential residues in stabilizing the ESAT-6 oligomer which provide useful insights for future drug design targeting tuberculosis. The approach in this research can also be used to model and study other cross-membrane complex structures.