Modeling and Simulation of Bacterial Outer Membranes and Interactions with Proteins

革兰氏阴性菌的外膜是一种独特的高度不对称的脂双层，由内叶的磷脂和外叶的脂多糖组成。虽然内毒素是主要成分，但OM中也含有肠杆菌共同抗原(ECAs)和荚膜多糖(CPS)，它们的存在经常被忽视。这些独特的细胞表面糖脂使OM成为有效的、选择性的屏障，阻止抗生素和胆盐等有毒分子渗透到细菌中，从而对公众健康造成重大威胁。这个项目试图通过最先进的分子建模和模拟来了解细菌OM的结构和动力学，以及它们与OM蛋白质的相互作用。该项目还将为OM分子建模和模拟的一般方法提供基础。特别是，该项目将通过教育推广、发表研究成果和参加研讨会来提高公众的科学素养。该项目旨在通过建立可靠的计算方法，对各种细菌的有机质的结构和动力学信息、蛋白质与有机质之间的相互作用以及它们对溶质渗透的影响提供前所未有的了解，从而为各种有机质中的革兰氏阴性细菌和膜蛋白的各种含LPS/ECA/CPS的复杂OM的全原子建模和模拟提供可靠的计算方法。它还寻求通过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(通过LPS/ECA/CPS模型器及其并入到膜生成器中的方法，www.charmm-gui.org)来促进关于LPS/ECA/CPS分子和细菌OM的协同科学研究和教育。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。

The outer membrane (OM) of Gram-negative bacteria is a unique and highly asymmetric lipid bilayer composed of phospholipids in the inner leaflet and lipopolysaccharides (LPS) in the outer leaflet. While LPS is the major component, the OM also contains the enterobacterial common antigens (ECAs) and capsular polysaccharides (CPS) whose occurrence is frequently overlooked. These unique cell surface glycolipids make the OM an effective, selective barrier against the permeation of toxic molecules such as antibiotics and bile salts into the bacteria, which causes significant threats to public health. This project seeks to acquire an understanding of structure and dynamics of the bacterial OMs and their interactions with the OM proteins using start-of-the-art molecular modeling and simulations. This project will also provide the basis for a general approach to OM molecular modeling and simulation. In particular, this project will raise the scientific literacy of the public through the educational outreach, publication of research results and workshop participation.This project aims to provide an in-depth and unprecedented understanding on structural and dynamics information of the OMs from various bacteria, interactions between proteins and OMs, and their influences on solute permeation by establishing reliable computational methods for all-atom modeling and simulation of various LPS/ECA/CPS-containing complex OMs of Gram-negative bacteria and membrane proteins in various OMs. It also seeks to foster synergistic scientific research and education on LPS/ECA/CPS molecules and bacterial OMs by providing reliable and general computational methods (through LPS/ECA/CPS Modelers and their incorporated into Membrane Builder in CHARMM-GUI, www.charmm-gui.org) to students and researchers in the simulation community and other disciplines.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.