Nearest-Neighbor Recognition in Lipid Bilayers

描述(由申请人提供)：项目摘要：“最近邻识别”(NNR)方法是一种很有前途的化学技术，它提供了对液体磷脂膜的横向组织的基本见解。本质上，NNR测量通过检测和量化脂质成为最近邻的趋势来获取膜组织的分子水平的快照。这项研究的具体目的是使用NNR方法来研究天然和非天然膜干扰剂存在下的脂肽相互作用、脂蛋白相互作用和脂脂相互作用。更具体地说，脂肽实验将是一项长期努力的一部分，旨在澄清根据流体双层中的脂类对外周和整体蛋白质进行分类的“规则”。脂质-蛋白质研究，结合跨双层磷脂相互作用，将提供对一个与细胞膜的结构和功能有直接关系的争议性很大的问题的洞察--这一问题几乎没有实验数据；也就是说，脂质双层的内外小叶之间的“通信”。最后，选定的全麻药和淀粉样β-肽对脂-脂相互作用的影响将提供对两个具有重大生物医学重要性的问题的基本见解；即，全麻药的作用机制和阿尔茨海默病的分子基础。该计划的长期目标是对流体双层的二维组织有一个基本的了解，这将有助于使生物膜中的可开发目标得到更清晰的关注。这种洞察力将有助于合理设计新型治疗剂。 相关性：细胞膜是细胞的“皮肤”，对维持生命状态是必不可少的。在分子水平上了解这些膜是如何在两个维度上组织起来的，应该有助于设计新的和改进的药物；例如，可用于治疗阿尔茨海默病的药物，用于打击酒精滥用的药物，以及可用作改进的全身麻醉剂的药物。该计划的目的是通过使用简单的模型系统来获得这样的理解。

DESCRIPTION (provided by applicant): PROJECT SUMMARY: The "nearest-neighbor recognition" (NNR) method is a promising chemical technique that provides fundamental insight into the lateral organization of fluid phospholipid membranes. In essence, NNR measurements take molecular-level snapshots of membrane organization by detecting and quantifying the tendency of lipids to become nearest-neighbors. The specific aims of this research are to use the NNR method to investigate lipid-peptide interactions, lipid-protein interactions, and lipid-lipid interactions in the presence of natural and unnatural membrane-perturbing agents. More specifically, lipid-peptide experiments will be part of a long-term effort aimed at clarifying the "rules" governing the sorting of peripheral and integral proteins by lipids in fluid bilayers. Lipid-protein studies, in combination with transbilayer phospholipid interactions, will provide insight into a much-debated issue that has a direct bearing on the structure and function of cell membranes-an issue for which there is virtually no experimental data; that is, the "communication" between the inner and outer leaflets of lipid bilayers. Finally, the effects of selected general anesthetics and amyloid beta-peptides on lipid-lipid interactions will provide fundamental insight into two problems that have major biomedical importance; that is, the mechanism by which general anesthetics function, and the molecular basis of Alzheimer's disease. The long-term objective of this program is to develop a fundamental understanding of the two-dimensional organization of fluid bilayers, which will help bring exploitable targets in biological membranes into sharper focus. Such insight will assist the rational design of novel classes of therapeutic agents. RELEVANCE: Cell membranes are "the skin" of cells, which are essential for maintaining the living state. Understanding how these membranes are organized in two dimensions, at the molecular level, should aid in the design of new and improved drugs; e.g., drugs that can be used to cure Alzheimer's disease, drugs to combat alcohol abuse, and drugs that can be used as improved general anesthetics. This program is aimed at obtaining such an understanding using simple model systems.