Generative protein design meets synthetic porphyrin assembly

De novo protein design has been used to create functional protein assemblies, but its reliance on standard amino acids limits the integration of synthetic supramolecular strategies for precise control of molecular assemblies. Herein, we present an artificial protein assembly that integrates synthetic supramolecular design with de novo protein engineering. Focusing on unit and connection rigidity, we designed and created the Bi-Porphyrin Acquisition Designer protein (BiPAD), which captures two highly designable synthetic porphyrins, via state-of-the-art generative protein design to fuse α/β-folded porphyrin-binding motifs. BiPADs captured rigid porphyrins, each bearing an additional metal coordination site, resulting in a metal-responsive cyclic assembly with the intended structure. Furthermore, high-speed atomic force microscopy revealed dynamic structural changes in the BiPAD assembly. This work expands the designability of artificial protein assemblies, paving the way for the synergistic design of functional systems through the integration of protein engineering and synthetic chemistry.