Molecular Modeling and Simulation of the Mycobacteria Cell Envelope

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Mycobacteria are generally non-motile bacteria covered by a protective envelope consisting of an outer cell membrane, a peptidoglycan layer and an inner membrane. This cell envelope provides the bacterial cell with structural integrity and protects the cell from hostile environments while allowing the transport of solutes and proteins. Despite its importance, our understanding of this envelope is rudimentary at best. Due to technical difficulties in deciphering these complex envelopes through experimentation, all-atom modeling and simulation should be able to provide an unprecedented understanding of the structure and dynamics of the mycobacterial cell envelope. This project aims to study the mycobacterial cell envelope by establishing reliable computational methods for all-atom molecular modeling and simulation of each constituent and their assembly. Undergraduate and graduate students will be directly involved in the research and an excellent outreach component includes community participation by use of the developed modeling platforms and sub modules. A large benefit to the scientific and general community is expected as the model will inspire new research and development of antimicrobial drugs.Although mycobacteria are Gram-positive bacteria, it is now well-known that their cell envelope is unique and has a mycobacterial outer membrane (MOM), a peptidoglycan (PG) layer, and a mycobacterial inner membrane (MIM), which is very similar to the cell envelope of Gram-negative bacteria. This project will provide an in-depth and molecular-level understanding of how different lipid compositions modulate the MIM and MOM properties, how the PG layer is connected to the MIM and MOM, and thus the overall structure of the mycobacterial cell envelope. It will also provide insight into how membrane proteins behave in and interact with the MIM or MOM. These results are significant and important to the field because there is no such molecular-level understanding (to the best of our knowledge). In addition, this project seeks to foster synergistic scientific research and education on the mycobacterial cell envelope and various lipid molecules unique to the MIM or MOM, by providing reliable and general computational methods through Membrane Builder in CHARMM-GUI to students and researchers in the simulation community and other disciplines.This works is jointly funded by the Cellular Dynamics and Function and Molecular Biophysics Clusters of MCB.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.