Chim, H. Y.; Idris, M. O.; Rieger, D.; Schlegel, P.; Goldbach, N. M.; Juanatey, M. A.; Mallik, B. B.; Buckley, S.; Basak, S.; Georgeon, S.; Lau, K.; Pojer, F.; Kaysser, L.; Tinnefeld, P.; Schoeder, C. T.; Correia, B. E.; Khmelinskaia, A.

Protein oligomers are ubiquitous in biological systems and essential for function. However, the de novo design of oligomers that controllably assemble in response to exogenous stimuli remains challenging. Here, we present an AI-based generative approach that leverages an interface-seeded strategy for designing responsive homo-oligomers from isolated interaction modules. Experimentally validated designs are highly accurate and explore new-to-nature topologies. We show that designs effectively respond to their chemical triggers with conditional oligomerization or to phosphorylation-driven conformational changes with reversible oligomerization. We further functionalized our responsive assemblies to build ligand-dependent membrane binding systems and phosphorylation-controlled gene regulatory switches. Our framework enables the generalizable design of responsive protein complexes, opening novel possibilities for the engineering of biosynthetic systems with sophisticated regulatory mechanisms.