AI-Designed 'WRAP' Proteins Solve Decades-Old Membrane Protein Solubility Problem, Opening Door to Syphilis Vaccine
核心洞察
David Baker's team at the UW Medicine Institute for Protein Design developed computationally designed proteins called WRAPs that keep membrane proteins stable and soluble in water without detergents.
WRAPs are genetically encoded and co-expressed with target membrane proteins, allowing researchers to bypass the cell membrane entirely without modifying the native protein sequence.
The technique was validated on Treponema pallidum (搜索) outer membrane proteins, long-resistant antigens that may now enable development of a syphilis (搜索) vaccine and new diagnostics.
Researchers at the University of Washington School of Medicine's Institute for Protein Design have unveiled a breakthrough technique that solves one of structural biology's most persistent challenges: keeping membrane proteins stable and soluble in water without detergents. The work, published July 2 in Science, introduces computationally designed protein coverings called WRAPs — Water-soluble Rosetta Fold-diffused Amphipathic Proteins — that shield the hydrophobic surfaces of membrane proteins and render them water-soluble while preserving their native structure.
"Membrane proteins are notoriously difficult to work with. We needed to find a way to keep them intact in water," said David Baker, professor of biochemistry at the University of Washington School of Medicine, director of the Institute for Protein Design, and senior author of the paper.
A detergent-free solution to a fundamental problem
Membrane proteins sit embedded in the lipid bilayer that separates a cell's interior from its external environment, acting as gatekeepers, signal receptors, and molecular transporters. Their hydrophobic surfaces repel water, making them insoluble and unstable outside the amphiphilic membrane environment. For decades, researchers have relied on detergents to extract these proteins, but the approach is cumbersome and introduces contaminants that limit downstream applications — particularly in vaccine development.
"The common approach is to use a detergent to detach such proteins from the membrane, but this method poses several problems: the detergent needs to stay with the protein of interest, and in the case of potential vaccines, the detergent is a contaminant," explained Ljubica Mihaljević, a Howard Hughes Medical Institute (搜索) Helen Hay Whitney Postdoctoral Fellow and lead author of the study.
While mutating membrane proteins to make them water-soluble is possible, doing so sacrifices the ability to study the protein's true, native structure. WRAPs circumvent both problems. These AI-designed proteins are genetically fused to their membrane-protein targets and co-expressed in Escherichia coli. Once translated, the membrane protein never reaches the cell membrane — the WRAP sequesters it instead, forming a protective barrier around the hydrophobic regions.
"Because WRAPs are genetically fused to their membrane-protein targets, and purified directly from the soluble fraction, they allow researchers to bypass the membrane altogether without having to modify native sequence," the researchers note.
Structural validation and syphilis (搜索) vaccine potential
The team validated the approach by obtaining a high-resolution 2.95 Å image of a WRAPed mycobacterial porin (搜索), a transmembrane channel protein through which dissolved nutrients flow. This structural confirmation demonstrates that WRAPs do not distort the native conformation of their targets.
A particularly compelling application involves Treponema pallidum (搜索), the bacterium that causes syphilis (搜索). The outer membrane proteins of this pathogen are prime vaccine antigens but have long resisted production and structural characterization due to their membrane-bound nature. WRAPs changed that by enabling stable, soluble antigens that can finally be characterized.
"Work on syphilis (搜索) vaccines, for example, has been stalled by difficulties in studying antigens from the outer membranes of the bacteria that cause this infection," the UW Medicine team stated. The WRAP-bound versions of these proteins could be deployed as possible antigens for a syphilis vaccine and may also enable new diagnostics.
Open science and broad applicability
The researchers have publicly released the WRAP code so that other scientists can apply the technique to their membrane proteins of interest. "I'm excited to release the code to the general public for people who have their favorite membrane protein and know the structure, or it can be predicted with AlphaFold, to use WRAPs for whatever application they like," Mihaljević said. "That's the best way to show that your science is working."
Baker emphasized the breadth of potential impact: "The capability provided by WRAPs opens many new possibilities for both research and therapeutic application," noting that the technique unlocks applications across vaccine, diagnostic, and drug development efforts by making membrane proteins experimentally accessible without compromising structural and functional features.
The work was supported by Coefficient Giving, the Gates Foundation, the National Institute of Allergy and Infectious Disease, the Howard Hughes Medical Institute (搜索), the Curci Foundation, and an Erwin Schrödinger Postdoctoral Fellowship. A patent application has been filed for the new methods and proteins described in the work. Co-lead authors alongside Mihaljević include David E. Kim, a research scientist in biochemistry, and Pooja Bandawane, a Ph.D. student in biochemistry, both at the UW School of Medicine.