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。一个普遍的假设是，内部空腔的占用稳定了蛋白质的结构和动力学，减少了正常功能所必需的构象自由。最初的工作很大程度上依赖于合成肽，从中获得了对麻醉剂结合的最小结构要求的见解。在这个周期中，将研究更多与生物学相关的模型。因此，在一个项目中，不仅将继续与合成目标结合，而且将根据内部腔的存在、分布和特征从蛋白质数据库中选择候选蛋白质，以检查挥发性麻醉剂的结合和稳定。此外，由于需要定位和表征麻醉在膜蛋白中的结合，大量的努力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优化使用合成束支架的麻醉剂结合位点，但现在包括新的设计插入到脂质双层。由于膜蛋白可能是重要的麻醉靶点，我们将进一步探索麻醉药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。本项目继续致力于用一系列表征良好的折叠模型来定义麻醉剂/蛋白质相互作用的热力学，以评估稳定性和展开表面积之间的关系。另一个项目将继续利用分子动力学模拟来描述麻醉大分子相互作用的结构和动力学特征。对脂质双分子层和简单可溶性螺旋束的初步研究将在逻辑上导致在脂质中捆绑的肽。最后，在一个新项目中，将用中子干涉法研究脂质束和蛋白质束的结构特征。这些结构研究将探讨麻醉结合的后果，以及验证大分子基质中的位置、方向和分布。核心和蛋白质合成支持这五个项目。

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.