Open AccessA computational model of ESAT-6 complex in membrane
Author(s) -
Chitra B. Karki,
Yuejiao Xian,
Yixin Xie,
Shengjie Sun,
Alan E Lopez-Hernandez,
Brenda Y Juarez,
Jun Wang,
Jianjun Sun,
Lin Li
Publication year - 2020
Publication title -
journal of theoretical and computational chemistry/journal of theoretical and computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.221
H-Index - 25
eISSN - 1793-6888
pISSN - 0219-6336
DOI - 10.1142/s0219633620400027
Subject(s) - esat 6 , oligomer , mycobacterium tuberculosis , chemistry , membrane , population , tuberculosis , biochemistry , medicine , environmental health , organic chemistry , pathology
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.