7/22/2026
July 2026: A landmark breakthrough in *Science* | AI-driven de novo design of WRAP soluble proteins, rewriting the fundamental paradigm for membrane protein extraction and purification
Membrane proteins account for approximately 30% of the proteins encoded by the human genome and serve as direct targets for more than 60% of marketed drugs. Core targets—including G protein-coupled receptors (GPCRs), ion channels, transporters, and outer membrane pore proteins—have consistently been at the heart of research in structural biology, innovative drug target discovery, and CRO-based in vitro protein preparation. However, for a long time, the dissolution of hydrophobic transmembrane regions and their conformational stability have represented the most significant technical bottleneck in the resolution of membrane proteins: traditional methodologies heavily rely on chemical detergents such as DDM, LMNG, and OG to solubilize the lipid bilayer of the cell membrane; these approaches not only tend to disrupt the native quaternary structure of membrane proteins and dissociate key endogenous binding lipids, but can also induce a series of issues, including protein aggregation, loss of activity, and severe orientation bias in cryo-electron microscopy particles. Although subsequent developments in MSP nanodiscs and SMA/SMALP polymer-based detergent-free systems have significantly improved stability, they still face limitations such as low reconstitution efficiency, poor batch-to-batch reproducibility, and difficulties in capturing ultra-large complexes during assembly. On July 2, 2026, the David Baker Group at the University of Washington published a landmark original study in *Science*, leveraging the top-tier protein AI model RFdiffusion to de novo design an amphiphilic water-soluble protein, WRAP (Water-soluble RFdiffused Amphipathic Protein). This work establishes a novel membrane protein solubilization and purification approach that is entirely independent of any chemical detergents, does not require in vitro lipid reconstitution, and can be achieved through gene co-expression—providing a disruptive solution for the structural determination of membrane proteins that are difficult to express, prone to inactivation, or highly sensitive to lipids via cryo-electron microscopy.
