Mechanisms of Interleaflet Coupling in Asymmetric Lipid Membranes

活细胞通过一层薄薄的双层脂质和叫做质膜的相关蛋白质与外界交流。这种膜的一个显著特征是它的两半在化学上是不同的：面向细胞内部内容物的脂质与面向外部环境的脂质非常不同。目前尚不清楚这种成分不对称在健康细胞的生命中起什么作用，但很明显，没有它，细胞就不能正常工作，而且它们确实消耗了宝贵的能量来积极地维持它。该项目旨在通过回答细胞膜的两半如何相互沟通和影响的基本问题来揭示细胞膜不对称的奥秘。这将通过系统地研究在不对称膜两侧发现的不同类型的脂质如何影响另一半的性质以及整个膜的性质来完成。由于膜的大部分功能来源于它所承载的蛋白质，研究人员还将研究驻留在膜上的蛋白质如何受到脂质不对称的影响。在这个项目的过程中，主要研究者将在实验和计算方法方面培训研究生和博士后研究人员，为他们在STEM领域的职业生涯做好准备。研究人员将通过会议报告和同行评议的出版物向科学界传达他们的发现，并将通过外展计划吸引公众，以提高对生物物理研究的认识和欣赏。两个双层小叶的组成不对称是大多数细胞膜的基本特性，包括包围细胞的质膜。尽管这种不对称对细胞活力至关重要，但人们对其在正常细胞功能中的作用知之甚少。该项目将阐明控制不对称模型膜两半之间通信的规则，从而改进基于膜的不对称脂质组成的功能表型预测。该项目的主要目标是使用中子散射技术来揭示每个小叶的结构和动力学特性如何响应脂质组成的变化，并将实验结果与原子模拟相结合，以了解导致这些变化的潜在分子机制。第二个目标是深入了解不对称膜如何适应跨膜蛋白的存在，以及蛋白质如何反过来对不对称脂质环境做出反应。脂质提供了生物膜的基本结构，蛋白质提供了大部分的功能；该项目将提供关于蛋白质-脂质相互作用在不对称膜的生物学相关背景下非常需要的信息。第三个目标是继续发展强大的技术，以制备和表征复杂的不对称囊泡，用于先进的质膜模型系统。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Living cells communicate with the outside world through a thin double layer of lipids and associated proteins called the plasma membrane. A remarkable feature of this membrane is that its two halves are chemically distinct: the lipids that face the internal contents of the cell are very different from the lipids that face the external environment. It is not clear what role this compositional asymmetry plays in the life of a healthy cell, yet it is clear that cells do not function properly without it, and indeed they expend valuable energy to actively maintain it. This project aims to shed light on the mystery of cell membrane asymmetry by answering the basic question of how the two halves of a membrane communicate with and influence each other. This will be accomplished through the systematic study of how the different types of lipids that are found on each side of an asymmetric membrane influence the properties of the other half, as well as the properties of the membrane as a whole. Because much of a membrane's functionality is derived from the proteins it hosts, the researchers will also investigate how a membrane-resident protein affects, and is in turn affected by lipid asymmetry. In the course of this project, the principle investigator will train graduate students and postdoctoral researchers in experimental and computational methods that will prepare them for careers in STEM fields. The researchers will communicate their findings to the scientific community through conference presentations and peer-reviewed publications and will also engage the public through an outreach program to enhance awareness of and appreciation for biophysical research.Compositional asymmetry of the two bilayer leaflets is a fundamental property of most cellular membranes, including the plasma membrane that surrounds the cell. Although this asymmetry is essential for cell viability, its role in normal cellular function is poorly understood. This project will elucidate the rules that govern communication between the two halves of asymmetric model membranes, leading to improved predictions of functional phenotypes based on the asymmetric lipid composition of a membrane. A primary goal of the project is the use of neutron scattering techniques to reveal how the structural and dynamical properties of each leaflet respond to changes in lipid composition, and to integrate the experimental results with atomistic simulations to inform on the underlying molecular mechanisms responsible for these changes. A second objective is to develop a deeper understanding of how asymmetric membranes adapt to the presence of a transmembrane protein, and how the protein responds in turn to an asymmetric lipid environment. While lipids provide the basic structure of biomembranes, proteins provide most of the functionality; this project will provide much needed information about protein-lipid interactions in the biologically relevant context of an asymmetric membrane. A third objective is the continued development of robust techniques for preparing and characterizing complex asymmetric vesicles for use as advanced plasma membrane model systems.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.