Computational Assembly of Beta Barrel Membrane Protein

β 桶膜蛋白的计算组装

基本信息

批准号：
7356031
负责人：
Jie Liang
金额：
$ 27.43万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7356031
关键词：
Acid Fast Bacillae Staining Method Address Amino Acids Animals Anthrax disease Anti-Bacterial Agents Binding Biochemical Bundling Burn injury Cations Centrifugation Class Collaborations Communicable Diseases Complement Computational algorithm Computer software Databases Detection Development Devices Disease Disease Outbreaks Dissection Emerging Communicable Diseases Engineering Environment Equilibrium Escherichia coli Evolution Exotoxins Genome Genomics Goals Gram-Negative Bacteria Gram-Positive Bacteria Hand Helix (Snails)Homologous Gene Individual Infection Internet Intervention Investigation Joints Kinetics Knowledge Lead Letters Leucine Zippers Libraries Literature Markov Chains Measurement Measures Medical Membrane Membrane Proteins Meningococcal meningitis Methodology Methods Mitochondria Modeling Molecular Conformation Mutagenesis Mutation Natural regeneration Neurotransmitters Nosocomial pneumonia Numbers Outcome Pathogenesis Pattern Pennsylvania Peptides Pharmaceutical Preparations Play Positioning Attribute Principal Investigator Process Proteins Public Health Publications Rate Reporting Research Research Design Research Personnel Research Project Grants Retinal Cone Retinal Pigments Rhodopsin Role Sales Sampling Score Side Site Sodium Staphylococcal Infections Statistical Models Structure Study models Sucrose Surgical wound System Testing Texas Training Transmembrane Domain Universities Vaccines Validation Work antimicrobial drug base beta barrel chromophore cold temperature computer studies design driving force drug development ear helix experience flash photolysis glutamyl-glutamic acid innovation insight molecular dynamics novel programs protein folding protein protein interaction protein purification protein structure research study sound symporter therapeutic target three dimensional structure toliprolol vaccine development

项目摘要

DESCRIPTION (provided by applicant): Beta-barrels are one of the two classes of membrane proteins. They are found in gram-negative bacteria, acid-fast gram-positive bacteria, pore-forming exotoxins, and mitochondria, and are an important class of therapeutic targets for infectious diseases. Knowledge of the three-dimensional structures of membrane beta-barrels will be critical for developing effective anti-bacterial drugs. Studying how beta-barrels organize in membranes will also provide important lessons on how membrane proteins fold in general. The goal of the proposed project is two-fold: 1) to gain understanding on how beta-barrel proteins are assembled in membrane environments through computational studies, and 2) to predict at genomic scale a large number of accurate structures. We plan to develop a multi-pronged approach to achieve these goals. The specific aims of this project are: a) identification of sequence and spatial motifs and anti-motifs in beta-barrel proteins for stability analysis, b) evolutionary analysis of beta-barrel membrane proteins for detection of remote structural homologs and functional regions, and c) large scale prediction of three-dimensional structures and assembly of beta-barrel proteins. This project complements experimental work by providing additional interpretation and explanation of experimental results. It will also generate further testable hypotheses for experimental investigations. The outcome of the proposed research includes novel sequence and spatial motifs useful for protein design, membrane beta-barrel-specific scoring matrices useful for remote homology detection, empirical potential functions for assessing beta-barrel stabilities, and a large number of predicted structures. In addition, it will produce computational algorithms, software, and databases that will be made publicly available for further studies. Many emerging infectious diseases pose serious threats to public health, including hospital-acquired pneumonia due to gram-negative bacteria, meningococcal meningitis, anthrax, and staphylococcal infections such as surgical wound and burn infections. We do not have adequate treatments to counter possible outbreaks of these infections, and it is urgent to develop antimicrobial drugs and vaccines to combat these threats. Because beta-barrel proteins play key roles in the pathogenesis of these infectious diseases, our proposed research will lead to new targets and new strategies in the development of drugs and vaccines.

描述（由申请人提供）：β-桶是两类膜蛋白之一。它们存在于革兰氏阴性菌、抗酸革兰氏阳性菌、成孔外毒素和线粒体中，是传染病的一类重要治疗靶点。了解膜 β 桶的三维结构对于开发有效的抗菌药物至关重要。研究β-桶如何在膜中组织也将为了解膜蛋白一般如何折叠提供重要的教训。该项目的目标有两个：1）通过计算研究了解β-桶蛋白如何在膜环境中组装，2）在基因组规模上预测大量准确的结构。我们计划制定多管齐下的方法来实现这些目标。该项目的具体目标是：a）鉴定β-桶蛋白中的序列和空间基序以及反基序以进行稳定性分析，b）β-桶膜蛋白的进化分析以检测远程结构同源物和功能区域，以及c) 大规模预测三维结构和β-桶蛋白的组装。该项目通过对实验结果提供额外的解释和解释来补充实验工作。它还将为实验研究产生进一步可检验的假设。拟议研究的成果包括用于蛋白质设计的新颖序列和空间基序、用于远程同源性检测的膜β桶特异性评分矩阵、用于评估β桶稳定性的经验势函数以及大量预测结构。此外，它将产生计算算法、软件和数据库，供公众使用以供进一步研究。许多新出现的传染病对公众健康构成严重威胁，包括革兰氏阴性菌引起的医院获得性肺炎、脑膜炎球菌性脑膜炎、炭疽以及手术伤口和烧伤感染等葡萄球菌感染。我们没有足够的治疗方法来应对这些感染可能爆发的情况，因此迫切需要开发抗菌药物和疫苗来应对这些威胁。由于β-桶蛋白在这些传染病的发病机制中发挥着关键作用，因此我们提出的研究将为药物和疫苗的开发带来新的靶点和新的策略。