Reply to “Where is the Macrocycle?” Correspondence on “Simultaneous Organic and Inorganic Host–guest Chemistry within Pillararene-Protein Cage Frameworks”

Our recent publication in Chem. Eur. J. 2022, 28, e202104341 has inspired Prof. Peter B. Crowley (P.C.) to write a Correspondence questioning the presented concept of electrostatic self-assembly. The offered criticism is twofold: 1) the role of the cationic pillar[5]arene macrocycle to act as molecular glue in the formation of electrostatically driven protein assemblies is questioned by arguing that the pillararene is not incorporated into the frameworks. 2) Later, P.C. speculates that when the frameworks form, the role of electrostatic interactions is not firmly established and cation-pi bonding is the more plausible interaction. In this response, the raised comments are addressed. We present direct experimental NMR evidence showing that the pillar[5]arene is incorporated into the frameworks. Furthermore, we discuss the electrostatic self-assembly and our ferritin-related research line more broadly and clarify the role of key experiments.