# Purifying Membrane Proteins within Native Lipid Bilayers

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $221,875

## Abstract

Membrane proteins (MPs) are important but arguably the most challenging biological molecules to study in
solution. One major concern with studies of MPs is the requirement for extraction from their native environment,
the membrane. Over several decades the chemistry and MP communities have contributed diverse membrane
mimetics that help to solubilize and stabilize MPs. Despite their broad applications, these membrane mimetics
do not fully replicate the native bilayer setting of MPs which contains hundreds of diverse lipids. This is a
fundamental issue because lipid bilayers and specific lipid interactions are crucial to the structural assembly and
function of many MPs. Notwithstanding, key challenges remain as to how to isolate and stabilize fragile MPs and
MP complexes with little disturbance to their conformation, oligomer assembly, and function, tasks that are
nevertheless crucial to structural, functional and drug interaction studies. To overcome these important
challenges in MP research, we propose to develop a strategy to directly enrich or purify MPs within small patches
of cell membranes. Our proposal exploits the favorable properties of two types of popular membrane reagents,
i.e. small molecule detergents and amphiphilic polymers, and meanwhile avoid their shortcomings in that 1)
detergent is effective and inevitably used to disperse cell membranes in most MP pruritions, but the detergent-
solubilized membrane patches are highly dynamic and unstable structures; and 2) an amphiphilic polymer
scaffold may entrap and stabilize a central bilayer patch, but most polymers used to stabilize MPs are ineffective
to disperse cell membranes. To resolve the dilemma, we propose an ex novo polymer design to encircle small
membrane domains by crosslinking detergents in situ, upon the dispersion of cell membranes. To establish the
feasibility of this approach, we will explore chemistry for detergent crosslinking to solubilize and stabilize small
patches of cell membranes (Aim 1) and validate chemical tools in the purification of diverse MPs (Aim 2). If
successful, our development will provide a completely new and versatile approach to preparing MPs in nearly
native environment. Achieving this goal together with new tool development will have a far-reaching impact on
many areas of MP research in which the isolation of MPs is needed.

## Key facts

- **NIH application ID:** 10132363
- **Project number:** 5R21GM137193-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Qinghai Zhang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $221,875
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132363

## Citation

> US National Institutes of Health, RePORTER application 10132363, Purifying Membrane Proteins within Native Lipid Bilayers (5R21GM137193-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10132363. Licensed CC0.

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