Improved protein binder design using beta-pairing targeted RFdiffusion 🚀 New preprint from David Baker!🚀 • A breakthrough in protein binder design: this study uses RFdiffusion conditioned to generate binders that form precise beta-strand pairings with polar protein targets, yielding binders with superior affinity and specificity. • The approach focuses on polar regions of target proteins, especially edge beta-strands, addressing the challenge of complementing hydrogen bond donors and acceptors that are otherwise exposed to water. • Designed binders achieved affinities ranging from 76 pM to mid-nanomolar, targeting therapeutically relevant proteins like KIT, PDGFRɑ, and ALK-2, with no significant off-target binding. • A co-crystal structure of a binder in complex with the KIT receptor confirms the computational accuracy of this new design method, showcasing near-perfect matching of the design model and real-world interactions. • This beta-strand focused method not only enhances the range of RFdiffusion’s capabilities but also expands the potential for developing new therapeutic binders targeting polar protein surfaces, such as those in cancer-related pathways. • The new design approach surpasses traditional methods, particularly in targeting polar regions and edge beta-strands in proteins like ALK-2, ALK-3, and PDGFRɑ, where previous techniques failed to generate effective binders. • The study demonstrates that beta-strand pairing conditioned designs have higher thermal stability and are more specific in binding compared to earlier models, making them valuable for therapeutic applications like receptor targeting and drug delivery. @UWproteindesign @SavvidesLab @StevenMBanik @TimothyPJenkins @Green_Ahn @MelBenard86 @kf_verstraete @SusanaVazTor @_JosephWatson @martin_toul 📜Paper: doi.org/10.1101/2024.10.11.6…