INTERACTION OF ANESTHETICS WITH MACROMOLECULES

描述（摘自申请）：本研究的长期目标是增强我们对吸入麻醉剂与负责麻醉状态的生物大分子之间相互作用的理解。该计划中的工作的一个一般假设是，内部空腔的占用稳定蛋白质结构和动力学，减少正常功能所需的构象自由度。最初的工作严重依赖于合成肽，从中深入了解麻醉剂结合的最低结构要求。在这个周期中，将研究更多的生物学相关模型。因此，在一个项目中，不仅将继续与合成靶点结合，而且将检查基于内腔的存在、分布和特征从蛋白质数据库中选择的候选蛋白质的结合和稳定性。此外，由于需要定位和表征膜蛋白中的麻醉剂结合，因此将致力于开发吸入麻醉剂的新型光标记模拟物。一个项目将继续努力，以优化麻醉剂结合位点使用合成束支架，但现在包括插入到脂质双层的新设计。由于膜蛋白可能是重要的麻醉靶点，因此有一个项目将进一步探讨麻醉剂对哺乳动物视紫红质结构和功能的影响及其相关的信号转导机制。本项目的继续工作旨在定义麻醉剂/蛋白质相互作用的热力学与一系列良好表征的折叠模型，以评估稳定性和未折叠表面积之间的关系。另一个项目将继续其目标，使用分子动力学模拟来表征麻醉大分子相互作用的结构和动力学特征。最初的工作与脂质双层和简单的可溶性螺旋束将逻辑上导致捆绑肽在脂质。最后，脂质和蛋白质束的结构特征将在一个新的项目中用中子干涉测量法进行研究。这些结构研究将探测麻醉剂结合的后果，以及验证大分子基质内的位置、取向和分布。核心和蛋白质合成支持五个项目。

DESCRIPTION (taken from application): The long term goal of this research is to enhance our understanding of the interactions between inhaled anesthetics ante biological macromolecules that are responsible for the state of anesthesia. A general hypothesis underlying the work in this program is that occupancy of internal cavities stabilizes protein structure and dynamics, reducing the conformational freedom necessary for normal function. Initial work relied heavily on synthetic peptides, from which insight into the minimal structural requirements for anesthetic binding was gained. In this cycle, more biologically relevant models will be studied. Thus, in one project, not only will binding to synthetic targets be continued, but protein candidates from the Protein Data Bank, selected based on the presence, distribution and character of internal cavities, will be examined for binding and stabilization by volatile anesthetics. Further, because of the need to locate and characterize anesthetic binding in membrane protein, considerable effort will be devoted to developing novel photolabel mimics of the inhaled anesthetics. One project will continue the effort to optimize anesthetic binding sites using synthetic bundle scaffolds, but now include new designs for insertion into lipid bilayers. Because of the probability that membrane proteins are important anesthetic targets, one project will further explore the effect of anesthetics on the structure and function of mammalian rhodopsin and its associated signal transduction mechanism. This project continue work aim at defining the thermodynamics of anesthetic/protein interactions with a series of well-characterized folding models to evaluate the relationship between stabilization and unfolded surface area. Another project will continue its aim of characterizing the structural and dynamic features of anesthetic macromolecular interactions using molecular dynamics simulations. Initial work with lipid bilayers and simple soluble helical bundles will logically lead to bundled peptides in lipid. Finally, the structural features of lipid, and protein bundles will be studied with neutron interferometry in one new project. These structural studies will probe the consequences of anesthetic binding, as well as verify the location, orientation and distribution within the macromolecular matrix. Cores, and for protein synthesis support the five projects.