METHOD TO DETERMINE LATERAL HETEROGENEITY IN BILAYERS

这项研究计划的重点是开发一种新的方法来 以脂类为基础的磷脂组织研究 形成同源二聚体的倾向。这项技术被称为最近- 邻居识别(NNR)。因为此方法提供了明确的 和流体双层内的定量信息，它代表了一种 独一无二的机会来解决以前没有的问题 是有可能的。这项研究的直接目标是 具有可交换性的二硫基磷脂二聚体的合成 模拟磷酸甘油、磷胆碱的单体单元， 磷乙醇胺和鞘磷脂。然后这些脂类就会 在NNR实验中用于检验以下假设：(1) 酯类和醚类磷脂的不相容性在以下条件下会得到增强 阴离子的头部基团被两性离子的取代。(2) 头基团电荷的差异可以提供脂质的驱动力 种族隔离。(3)头部基团区域内的氢键，还 甘油的主干，可以促进侧向的异质性。(4) 磷脂和整体肽之间的疏水不匹配可能 诱导脂质聚集。(5)阳离子多肽的存在可以 促进阴离子与两性离子的横向分离 磷脂。此外，还将努力延长NNR 方法用于更复杂和更具生物相关性的膜，如 重组的红细胞幽灵。这样做的长期目标是 计划是发展对二维的基本理解 与生理相关的磷脂膜的组织 流体相。原则上，这样的理解应该有助于带来 可利用的靶点(例如，癌细胞的质膜， 细菌细胞和真菌细胞)进入更清晰的焦点，这可以 协助合理设计新型治疗剂。

This research program focuses on the development of a new approach to the study of phospholipid organization that is based on the lipid's tendency to form homodimers. This technique has been termed, nearest- neighbor recognition (NNR). Because this method provides unambiguous and quantitative information within fluid bilayers, it represents a unique opportunity for addressing questions that have not previously been possible. The immediate objectives of this research are to synthesize disulfide-based phospholipid dimers that bear exchangeable monomer units that mimic phosphoglycerols, phosphocholines, phosphoethanolamines, and sphingomyelins. These lipids will then be used in NNR experiments to test the following hypotheses: (1) The immiscibility of ester and ether phospholipids will be enhanced when anionic head groups are replaced by ones that are zwitterionic. (2) Differences in head group charge can provide a driving force for lipid segregation. (3) Hydrogen bonding within the head group region, and also the glycerol backbone, can promote lateral heterogeneity. (4) Hydrophobic mismatch between phospholipids and integral peptides can induce lipid clustering. (5) The presence of cationic peptides can promote the lateral separation of anionic from zwitterionic phospholipids. In addition, efforts will be made to extend the NNR method to more complex and more biologically-relevant membranes such as reconstituted erythrocyte ghosts. The long-term objective of this program is to develop a fundamental understanding of the two-dimensional organization of phospholipid membranes in the physiologically-relevant fluid phase. In principle, such an understanding should help to bring exploitable targets (e.g., the plasma membrane of cancer cells, bacterial cells, and fungal cells) into sharper focus, which could assist the rational design of novel classes of therapeutic agents.