Lin, Y.; Lee, M.; Vermani, A.; Jiang, E.; De Cooman, S.; Spetko, M.; AlQuraishi, M.

Despite the breakneck pace of progress in protein design methodology, frontier problems remain challenging, with leading methods struggling to design high-affinity binders, scaffold multiple functional motifs, or stabilize large multi-domain proteins. Recent research efforts have focused on two areas: improving model reasoning when generating active sites or binding interfaces, and improving concordance between the design process and the in silico oracle used to select promising designs. In addressing the first, the field has shifted towards all-atom models that capture sidechain conformations in atomistic detail by eschewing data-efficient SE(3)-equivariance, mirroring the evolution of AlphaFold2 to AlphaFold3. In addressing the second, recent work has focused on replacing generative models employing diffusion or flow-matching with hallucination approaches that directly optimize the oracle in sequence space; this improves success rates but reduces computational efficiency. Here, we close and surpass the generation-hallucination gap by revisiting SE(3)-equivariance using a branched polymer treatment of protein structures. The resulting diffusion model, Genie 3, achieves state-of-the-art performance on binder design, motif scaffolding, and unconditional generation, while being significantly faster than the best existing methods. We use Genie 3 to design a nanomolar binder of Nipah Glycoprotein G, a tetramer with minimal structural or biophysical characterization, as part of the Adaptyv Bio Nipah Competition, achieving a 12.5% success rate. Taken together, our results present a new frontier in protein design capability and a reexamination of the role of SE(3)-equivariance in molecular modeling.