Molecular Modeling and Simulation of the Mycobacteria Cell Envelope

分枝杆菌通常是由保护性包膜覆盖的非运动细菌，所述保护性包膜由外细胞膜、肽聚糖层和内膜组成。这种细胞包膜为细菌细胞提供了结构完整性，并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。尽管它的重要性，我们对这个信封的理解充其量是初步的。由于通过实验破译这些复杂包膜的技术困难，全原子建模和模拟应该能够提供对分枝杆菌细胞包膜的结构和动力学的前所未有的理解。本计画旨在建立可靠的计算方法，以全原子分子模式化及模拟分枝杆菌细胞膜的各组成部分及其组装。本科生和研究生将直接参与研究，一个优秀的外展部分包括通过使用开发的建模平台和子模块的社区参与。尽管分枝杆菌是革兰氏阳性菌，但众所周知，它们的细胞被膜是独特的，具有分枝杆菌外膜（mycobacterial outer membrane，简称MCE）、肽聚糖（peptidoglycan，简称PG）层和分枝杆菌内膜（mycobacterial inner membrane，简称MIM），这与革兰氏阴性菌的细胞被膜非常相似。该项目将提供深入和分子水平的理解，不同的脂质成分如何调节MIM和MIM特性，PG层如何连接到MIM和MIM，从而分枝杆菌细胞包膜的整体结构。它还将提供深入了解膜蛋白如何在MIM或MIM中表现并与MIM或MIM相互作用。这些结果对该领域来说是重要的，因为没有这样的分子水平的理解（据我们所知）。此外，该项目旨在促进关于分枝杆菌细胞包膜和MIM或MIM特有的各种脂质分子的协同科学研究和教育，通过CHARMM中的Membrane Builder提供可靠和通用的计算方法，图形用户界面的学生和研究人员在模拟社区和其他学科。这项工作是由细胞动力学和功能和分子生物物理集群的MCB共同资助。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.