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Modeling and Simulation of Bacterial Outer Membranes and Interactions with Proteins

细菌外膜及其与蛋白质相互作用的建模和模拟

基本信息

批准号：
1810695
负责人：
Wonpil Im
金额：
$ 61.67万
依托单位：
Lehigh University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1810695&HistoricalAwards=false
关键词：
Modeling Simulation Bacterial Outer Membranes

项目摘要

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.

革兰氏阴性菌的外膜（OM）是一种独特且高度不对称的脂质双层，由内小叶中的磷脂和外小叶中的脂多糖（LPS）组成。虽然LPS是主要成分，但OM还含有肠细菌共同抗原（ECA）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成为有效的选择性屏障，防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。该项目旨在利用最先进的分子建模和模拟来了解细菌OM的结构和动力学及其与OM蛋白的相互作用。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，本计划将透过教育披索、出版研究成果及参与工作坊，提高公众的科学素养，让公众对各种细菌有机分子的结构及动力学信息、蛋白质与有机分子的相互作用、及其对溶质渗透的影响，通过建立可靠的计算方法，全原子建模和模拟各种LPS/ECA/CPS含有复杂的有机分子的革兰氏-阴性细菌和膜蛋白。它还旨在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 Modelers及其纳入CHARMM-GUI，www.example.com中的Membrane Builder），促进LPS/ECA/CPS分子和细菌OM的协同科学研究和教育www.charmm-gui.org。该奖项反映了NSF的法定使命，并通过使用基金会的学术价值和更广泛的影响审查标准。