Mechanisms of Interleaflet Coupling in Asymmetric Lipid Membranes

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.