Supramolecular chemistry has primarily found its inspiration in biological molecules, such as proteins and lipids, and their interactions. Currently the supramolecular assembly of designed compounds can be controlled to great extent. This provides the opportunity to combine these synthetic supramolecular elements with biomolecules for the study of biological phenomena. This tutorial review focuses on the possibilities of the marriage of synthetic supramolecular architectures and biological systems. It highlights that synthetic supramolecular elements are for example ideal platforms for the recognition and modulation of proteins and cells. The unique features of synthetic supramolecular systems with control over size, shape, valency, and interaction strength allow the generation of structures fitting the demands to approach the biological problems at hand. Supramolecular chemistry has come full circle, studying the biology and its molecules which initially inspired its conception.

A supramolecular strategy is used for oriented positioning of proteins on surfaces. A viologen-based guest molecule is attached to the surface, while a naphthol guest moiety is chemoselectively ligated to a yellow fluorescent protein. Cucurbit[8]uril (CB[8]) is used to link the proteins onto surfaces through specific charge-transfer interactions between naphthol and viologen inside the CB cavity. The assembly process is characterized using fluorescence and atomic force microscopy, surface plasmon resonance, IR-reflective absorption, and X-ray photoelectron spectroscopy measurements. Two different immobilization routes are followed to form patterns of the protein ternary complexes on the surfaces. Each immobilization route consists of three steps: (i) attaching the viologen to the glass using microcontact chemistry, (ii) blocking, and (iii) either incubation or microcontact printing of CB[8] and naphthol guests. In both cases uniform and stable fluorescent patterns are fabricated with a high signal-to-noise ratio. Control experiments confirm that CB[8] serves as a selective linking unit to form stable and homogeneous ternary surface-bound complexes as envisioned. The attachment of the yellow fluorescent protein complexes is shown to be reversible and reusable for assembly as studied using fluorescence microscopy.

Two sets of cyan and yellow fluorescent proteins, monomeric analogues, and analogues with a weak affinity for dimerization were functionalized with supramolecular host-guest molecules by expressed protein ligation. The host-guest elements induce selective assembly of the monomeric variants into a supramolecular heterodimer. For the second set of analogues, the supramolecular host-guest system acts in cooperation with the intrinsic affinity between the two proteins, resulting in the induction of a selective protein-protein heterodimerization at a more dilute concentration. Additionally, the supramolecular host-guest system allows locking of the two proteins in a covalent heterodimer through the facilitated and selective formation of a reversible disulfide linkage. For the monomeric analogues this results in a strong increase of the energy transfer between the proteins. The protein heterodimerization can be reversed in a stepwise fashion. The trajectory of the disassembly process differs for the monomeric and dimerizing set of proteins. The results highlight that supramolecular elements connected to proteins can both be used to facilitate the interaction between two proteins without intrinsic affinity and to stabilize weak protein-protein interactions at concentrations below those determined by the actual affinity of the proteins alone. The subsequent covalent linkage between the proteins generates a stable protein dimer as a single species. The action of the supramolecular elements in concert with the proteins thus allows the generation of protein architectures with specific properties and compositions.