Molecular Modeling and Simulation of the Mycobacteria Cell Envelope

分枝杆菌通常是由保护膜覆盖的非运动性细菌，保护膜由外细胞膜、肽聚糖层和内膜组成。这种细胞膜为细菌细胞提供结构完整性，保护细胞免受恶劣环境的影响，同时允许溶质和蛋白质的运输。尽管它很重要，但我们对这个信封的理解充其量也是初级的。由于通过实验破译这些复杂的包膜存在技术困难，全原子建模和模拟应该能够提供对分枝杆菌细胞包膜结构和动力学的前所未有的了解。该项目旨在通过建立可靠的计算方法来研究分枝杆菌的细胞膜，以便对每个组分及其组装进行全原子分子建模和模拟。本科生和研究生将直接参与研究，一个很好的推广部分包括通过使用开发的建模平台和子模块进行社区参与。虽然分枝杆菌是革兰氏阳性细菌，但众所周知，它们的细胞膜是独特的，具有分枝杆菌外膜(MOM)、肽聚糖(PG)层和分枝杆菌内膜(MIM)，这与革兰氏阴性细菌的细胞膜非常相似。该项目将在分子水平上深入了解不同的脂质成分如何调节MIM和MOM的性质，PG层如何连接到MIM和MOM，从而了解分枝杆菌细胞膜的整体结构。它还将提供对膜蛋白在MIM或MOM中的行为和相互作用的洞察。这些结果对该领域意义重大，因为(据我们所知)还没有这样的分子水平的理解。此外，这个项目致力于促进对MIM或MOM特有的分枝杆菌细胞膜和各种脂质分子的协同科学研究和教育，通过CHARMM-图形用户界面中的膜生成器向模拟社区和其他学科的学生和研究人员提供可靠和通用的计算方法。这项工作由MCB的细胞动力学和功能和分子生物物理学集群共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.