LAUSR

Significance The ability of chemists to regulate the concentration of molecules is extremely important. However, as reactions are slowly superseded by more complex reaction networks, new ways of regulating molecular concentrations are needed. Recently, we described a system in which the concentration of a monovalent molecule with catalytic activity was buffered over a wide concentration range by its binding to a divalent molecule. Guided by model predictions, we are able to experimentally optimize the system by increasing the valency of the buffer, with even-numbered valencies displaying superior buffering capabilities. These results allow us to understand and gain more control over the activities of molecules in complex molecular systems, thereby obtaining insights into natural systems as well as creating adaptive artificial systems. A supramolecular system in which the concentration of a molecule is buffered over several orders of magnitude is presented. Molecular buffering is achieved as a result of competition in a ring–chain equilibrium of multivalent ureidopyrimidinone monomers and a monovalent naphthyridine molecule which acts as an end-capper. While we previously only considered divalent ureidopyrimidinone monomers we now present a model-driven engineering approach to improve molecular buffering using multivalent ring–chain systems. Our theoretical models reveal an odd–even effect where even-valent molecules show superior buffering capabilities. Furthermore, we predict that supramolecular buffering can be significantly improved using a tetravalent instead of a divalent molecule, since the tetravalent molecule can form two intramolecular rings with different “stabilities” due to statistical effects. Our model predictions are validated against experimental 1H NMR data, demonstrating that model-driven engineering has considerable potential in supramolecular chemistry.