Project 3

3.3.背景和意义 3.3.1。迫切需要针对MP结构生物学进行优化的新型模型膜介质。到目前为止，通过核磁共振或结晶学方法确定的绝大多数MP结构是使用经典洗涤剂作为模型膜介质确定的。不幸的是，即使是温和的洗涤剂也会破坏MPS在天然膜中的稳定性。此外，许多最温和的洗涤剂(如烷基麦芽糖苷)通常无法产生高质量的核磁共振谱。更多的天然介质，如洗涤剂-脂类混合胶束或双胶束，有时提供优势，但也有缺点。此外，尽管来自高等生物体的膜几乎总是含有相当大的摩尔分数的胆固醇，但很少有人开展工作来建立含有胆固醇的与核磁共振兼容的介质，部分原因是它在洗涤剂溶液中的溶解度非常低。显然，有必要扩大可用的仿膜介质的范围。我们建议设计、合成(通过核心B)和测试用于MPS结构生物学研究的新表面活性剂。我们还将测试表面活性剂 和胆固醇类似物，最近已经商业化，但尚未得到很好的测试。

3.3. Background and Significance 3.3.1. There is a compelling need for novel model membrane media that are optimized for MP structural biology. The vast majority of MP structures determined to date by either NMR or crystallographic methods were determined using classical detergent as the model membrane media. Unfortunately, even mild detergents destabilize MPs relative to their stability in native membranes. Moreover, many of the mildest detergents (such as the alkyl maltoside) routinely fail to yield high quality NMR spectra. More native-like media, such as detergent-lipid mixed micelles or bicelles sometimes offer advantages, but also have drawbacks. Moreover, while membranes from higher organisms almost always contain a considerable mole fraction of cholesterol, very little work has been carried out to establish NMR-compatible media that contain cholesterol, in part because of its very low solubility in detergent solutions. It is clear that there is a need to expand the range of membrane-mimetic media that are available. We propose to design, synthesize (through Core B) and test new surfactants for use in structural biological studies of MPs. We also will test surfactants and cholesterol analogs that have recently been commercialized but not yet well tested.