Diffusing protein binders to intrinsically disordered proteins using RFdiffusion

This video summarizes the paper “Diffusing protein binders to intrinsically disordered proteins” by Liu et al., Nature (2025) (PMID: 39071267). The authors present a method using RFdiffusion to design protein binders that can specifically target intrinsically disordered proteins (IDPs) or regions (IDRs) by freely sampling both target and binder conformations. The approach succeeds in generating binders to IDPs such as amylin, C-peptide, VP48, G3BP1, IL2RG, and prion proteins with affinities in the 3–100 nM range. Some designed binders disrupt amyloid fibers, modulate stress granule formation, or colocalize with receptors in cells. This strategy may expand our ability to target flexible, structure-heterogeneous protein systems for diagnostics or therapeutics.