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Fast and Ultra-Capable Protein Design: Advancing the Frontier Through Atomistic SE(3)-Equivariance with Genie 3 | bioRxiv

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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 cl

New Results , Minji Lee, Aakarsh Vermani, Ellena Jiang, Sebastiaan De Cooman, Matej Špeťko, Mohammed AlQuraishi doi: https://doi.org/10.64898/2026.05.01.722168 Abstract 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…

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