Nearest-Neighbor Recognition in Lipid Bilayers

项目概述：“最近邻识别”（NNR）方法是一种很有前途的化学技术，它提供了对流体磷脂膜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居的趋势来获取膜组织的分子水平快照。本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质-肽相互作用、脂质-蛋白相互作用以及脂质-脂质相互作用。更具体地说，脂质肽实验将是一项长期努力的一部分，目的是澄清液体双层中脂质对外周蛋白和整体蛋白进行分类的“规则”。脂质-蛋白质研究，结合跨双层磷脂相互作用，将提供对一个备受争议的问题的见解，这个问题对细胞膜的结构和功能有直接的影响，这个问题实际上没有实验数据；即脂质双分子层的内外小叶之间的“通讯”。最后，选定的全身麻醉剂和淀粉样β肽对脂质相互作用的影响将为两个具有重要生物医学意义的问题提供基本见解；也就是说，全身麻醉剂的作用机制，以及阿尔茨海默病的分子基础。该计划的长期目标是发展对流体双层二维组织的基本理解，这将有助于将生物膜中的可利用目标纳入更清晰的焦点。这种见解将有助于合理设计新型治疗剂。

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.