Abstract Membranes proteins are essential molecules to support cell growth, mediate signal transduction, and maintain homeostasis. They are either associated with, or embedded in the lipid bilayer, thus exhibit complex chemical properties and present formidable challenges for biophysical studies. Over the past few decades, enormous efforts have focused on providing mechanistic insights into these sophisticated macromolecules. However, the progress is hampered by the lack of robust tools to facilitate structural and functional studies for membrane proteins. Moreover, the water-insoluble lipid bilayer makes it notoriously difficult to modulate these proteins for therapeutic purposes. To address these problems, the proposed research aims to develop next-generation nanodiscs that enact simple and straightforward interrogation and modulation of membrane proteins. First, we will develop a detergent- free nanodisc system to ease the isolation of integral membrane proteins from their native lipid environment. Second, we will engineer nanodisc reporters to allow rapid and label-free detection of membrane binding and remodeling activities of peripheral membrane proteins. Finally, we will build fusogenic and switchable nanodiscs to drug membrane proteins with unprecedented specificity and efficacy. Together, these simple and versatile tools will significantly transform the field of membrane biochemistry and shed new light on membrane proteins that were previously thought to be unapproachable or undruggable.

Narrative Membrane proteins underlie the cause of many human diseases and thus comprise over 60% of current drug targets. However, they are much less understood than soluble proteins due to technical challenges associated with their isolation and characterization. The proposed research seeks to develop a toolkit of next-generation nanodiscs that would revolutionize structural, functional, and translational studies of membrane proteins and their related diseases.