Computational Assembly of Beta Barrel Membrane Protein

描述(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、形成毛孔的外毒素和线粒体中，是一类重要的感染性疾病治疗靶点。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，也将为膜蛋白如何折叠提供重要的经验教训。该项目的目标有两个：1)通过计算研究了解β-桶蛋白在膜环境中是如何组装的；2)在基因组水平上预测大量的准确结构。我们计划制定一个多管齐下的方法来实现这些目标。该项目的具体目标是：a)确定β-桶蛋白中的序列、空间基序和反基序以进行稳定性分析；b)对β-桶蛋白进行进化分析以检测远程结构同源物和功能区；以及c)大规模预测β-桶蛋白的三维结构和组装。本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更多可验证的假说。该研究的成果包括用于蛋白质设计的新的序列和空间基序、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的结构。此外，它还将制作计算算法、软件和数据库，供公众进一步研究。许多新出现的传染病对公众健康构成严重威胁，包括由革兰氏阴性细菌引起的医院获得性肺炎、脑膜炎双球菌脑膜炎、炭疽病和葡萄球菌感染，如外科伤口和烧伤感染。我们没有足够的治疗方法来应对这些感染的可能爆发，迫切需要开发抗微生物药物和疫苗来对抗这些威胁。由于β-桶蛋白在这些传染病的发病机制中起着关键作用，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。

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.