New Computational Strategy Sheds Light on Membrane Protein Function
Membrane proteins orchestrate essential cellular tasks, from moving substances across the lipid bilayer to transmitting signals and aiding cell-to-cell interactions. When these proteins malfunction, it can lead to diseases including cancer, making them prime targets for therapeutics. Yet studying their behavior is notoriously challenging because their home is the cell membrane—an intricate, lipid environment that keeps them tightly packed and difficult to observe outside the cell.
Researchers at Scripps Research have introduced a computer-driven strategy to reveal how membrane proteins work at the atomic level. Published in PNAS on October 7, 2025, their work designs synthetic membrane proteins that are easier to study in the lab while uncovering structural rules that help some proteins maintain their shape.
Designing Stable Models to Decode Complex Biology
The team focused on a recurring structural motif found in many membrane proteins: a Gly-X6-Gly sequence repeating every seven residues as the polypeptide traverses the membrane. This pattern places small amino acids at the same position on every second turn of the helix, suggesting these motifs act as “sticky spots” that stabilize interactions between helices within the lipid environment.
Using advanced computational tools, senior author Marco Mravic and colleagues designed idealized versions of this motif to test in the laboratory. The goal was twofold: create synthetic membrane proteins with enhanced stability and reveal why the motif contributes so strongly to structural integrity in membrane-embedded proteins.
From Computer Models to Lab-Validated Proteins
First author Kiana Golden developed software to identify sequences containing the Gly-X6-Gly motif and used this information to engineer synthetic membrane proteins with optimized stability. When produced and studied experimentally, these synthetic proteins folded as predicted, validating the hypothesis that the motif acts as a stabilizing hub between adjacent helices.
Remarkably, the team found that the stability of the motif is driven by an unusual hydrogen-bonding network. Although the bonds are individually weak, their repetition across the motif creates a cumulative stabilizing effect. This explains why natural evolution has favored this particular arrangement across diverse membrane proteins.
Implications for Disease, Drug Development, and Beyond
Understanding how this motif sustains membrane protein structure has practical consequences. It can help scientists interpret how genetic mutations might disrupt function and contribute to disease. Moreover, the demonstrated ability to design robust protein complexes in lipid environments accelerates the development of molecules that target membrane proteins directly inside cells. Such advances could broaden therapeutic options for diseases driven by membrane protein dysfunction.
“Our approach vastly accelerates what we can discover about the inner workings of membrane proteins and how to make better therapies,” says Mravic. By combining computational design with experimental validation, the researchers have established a framework for exploring membrane protein behavior that was once difficult to observe outside the cellular context.
What’s Next for This Research
With the proof of concept in place, the team is pursuing several avenues. They are refining their software to design even more complex membrane proteins and planning studies to create molecules that directly target membrane proteins within the cell. The work points toward a future where computational strategies inform drug design and synthetic biology in ways that were previously unattainable.
Reference: Golden K, Avarvarei C, Anderson CT, et al. Design principles of the common Gly-X6-Gly membrane protein building block. PNAS. 2025;122(41):e2503134122. doi: 10.1073/pnas.2503134122
