Scheme showing the iterative engineering of a soluble, non-self-associating protein building block by MDPSA and MeTIR. By MDPSA, chelating motifs (e.g., bis-His clamps) can be incorporated into the protein surface, enabling the formation of metal-directed oligomers. By MeTIR, the nascent interfaces in these oligomers can be reinforced with the installation of complementary PPIs to generate self-assembling complexes that can form in the absence of templating metals. The installation of disulfide crosslinks increases scaffold robustness and the fidelity of self-assembly. These robust scaffolds can accommodate reactive metal sites to generate de novo designed metalloenzymes.