Unraveling the Mysteries of Membrane Proteins
Membrane proteins are essential gatekeepers of the cell, orchestrating substance transport, signal transduction, and intercellular adhesion. When their function goes awry, diseases such as cancer can arise, making these proteins prime targets for therapies. Yet studying membrane proteins is notoriously difficult because their lipid surroundings help them hide their true behavior. A team from Scripps Research has now developed a computer-driven strategy to illuminate how these proteins work at the atomic level by building and testing synthetic versions in the lab.
Designing Synthetic Proteins to See the Unseeable
Published in PNAS on October 7, 2025, the study focuses on a recurring pattern in many membrane proteins: a Gly-X6-Gly motif that repeats every seven amino acids as the protein chain crosses the lipid bilayer. The researchers hypothesized that these motifs act as “sticky spots” that promote tight helix-helix interactions, helping the protein stay correctly folded within the membrane.
To test this, first author Kiana Golden developed software to identify sequences containing the motif and then designed optimized synthetic membrane proteins with enhanced stability. When produced in the lab, these synthetic analogs folded as predicted, supporting the idea that repeated motifs create stable interfaces within the membrane.
The Atomic Insight: Weak Bonds, Strong Stability
Golden’s work revealed that the motif’s stability is driven by a rare type of hydrogen bond. While individual hydrogen bonds in this context are weak, chaining the motif across multiple turns amplifies the interaction, resulting in a surprisingly robust complex. “This unusual hydrogen-bonding pattern, when repeated, builds a durable network that helps the helices stay together in the lipid environment,” Golden explained.
These findings were validated by designing synthetic proteins with the most favorable sequences, which exhibited remarkable stability and even withstood boiling conditions in some cases. The study thus uncovers a new principle: the concerted action of weak hydrogen bonds, when organized in a specific repeating motif, underpins membrane protein architecture.
Implications for Disease, Drug Design, and Biotechnology
Understanding the Gly-X6-Gly motif offers researchers a concrete rule set for predicting how membrane proteins fold and interact. This knowledge can help identify genetic mutations that disrupt stability and contribute to disease. More broadly, the demonstrated ability to design sturdy synthetic membrane proteins opens avenues for drug discovery, therapeutic design, and biotechnology that targets these proteins directly within cells.
Mravic, senior author and an assistant professor at Scripps Research, emphasizes the potential impact: “Our approach vastly accelerates what we can discover about the inner workings of membrane proteins and how to make better therapies.” The method bridges computational design with experimental validation, producing model proteins that reveal fundamental rules of membrane biology while serving as platforms for future drug targets.
What Comes Next
With the software proven capable of constructing robust membrane-embedded protein complexes, the team is now pursuing designs of molecules that can selectively modulate membrane proteins in living cells. These designer proteins not only illuminate basic biology but also lay the groundwork for targeted therapies that address diseases rooted in membrane protein dysfunction.
Collaborators and Publication
Beyond Marco Mravic and Kiana Golden, the study, titled “Design principles of the common Gly-X6-Gly membrane protein building block,” includes Catalina Avarvarei, Charlie T. Anderson, Matthew Holcomb, Weiyi Tang, Xiaoping Dai Minghao Zhang, Colleen A. Mailie, Brittany B. Sanchez, Jason S. Chen, and Stefano Forli from Scripps Research.
