Molecular Modeling and Simulation of the Mycobacteria Cell Envelope

分枝杆菌通常是一种不活动的细菌，被一层由外细胞膜、肽聚糖层和内膜组成的保护膜所覆盖。这种细胞包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只是初步的。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结构和动力学的前所未有的理解。本项目旨在通过建立可靠的计算方法来研究分枝杆菌细胞包膜的全原子分子建模和模拟每个组成部分及其组装。本科生和研究生将直接参与研究，通过使用开发的建模平台和子模块，社区参与是一个很好的外展组成部分。由于该模型将激发新的抗微生物药物的研究和开发，预计科学界和一般社区将从中受益。虽然分枝杆菌是革兰氏阳性菌，但众所周知，它们的细胞包膜是独特的，具有分枝杆菌外膜（MOM）、肽聚糖（PG）层和分枝杆菌内膜（MIM），这与革兰氏阴性菌的细胞包膜非常相似。该项目将提供对不同脂质组成如何调节MIM和MOM性质的深入和分子水平的理解，PG层如何连接到MIM和MOM，从而了解分枝杆菌细胞包膜的整体结构。它还将提供关于膜蛋白如何在MIM或MOM中表现和相互作用的见解。这些结果对该领域来说意义重大，因为（据我们所知）没有这样的分子水平的理解。此外，本项目旨在通过CHARMM-GUI中的Membrane Builder为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，促进分枝杆菌细胞包膜和MIM或MOM特有的各种脂质分子的协同科学研究和教育。本研究由MCB细胞动力学与功能和分子生物物理集群共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值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.