Molecular self-assembly is the process in which molecules combine into superstructures held together through non-covalent interactions. Over the last decades, supramolecular chemists have perfected this art, and we can now create Gigadalton structures in which each atom is placed with angstrom precision. More importantly, the unique properties of the emerging assemblies have found their way in everyday life like, for example, the liquid crystals in our displays. Nevertheless, we are completely overshadowed by biology when it comes to assembly with molecular building blocks. Indeed, the biological cell has the same molecular toolbox at its disposal for creating structures; it also uses non-covalent interactions to hold molecules together. While the building blocks themselves may be more sophisticated and biology use hundreds of different components, there is no reason to believe that we should also be able to do so in the future. Yet, something is missing. If we were to synthesize hundreds of building blocks and mix them in the right order, we would not create a biological cell. We would not be able to synthesize life using molecular self-assembly alone.
Biology uses another trick. Biological structures are governed not only by non-covalent interactions but also by reactions forming covalent ones. Arguably, molecular self-assembly offers the structures; chemical reactions govern the dynamics of these structures. For example, once a protein has folded and assembled into its desired structure, its dynamic and function are regulated through chemical reactions like phosphorylation and dephosphorylation or oxidation and reduction. These reactions are typically cyclical, such that a protein is used over and over for its function, while only some reagents of the reaction cycle are converted. The assembly of the protein tubulin into microtubules is an illustrative example. Tubulin by itself does not assemble. To assemble into microtubules, tubulin is required to bind GTP first. After self-assembly, neighboring tubulin will hydrolyze the GTP into GDP, which will result in its disassembly. Thus, by coupling the self-assembly to a GTP-hydrolyzing reaction cycle, tubulin was only temporarily activated and, therefore, only temporarily part of the self-assembly. While this costs chemical energy, it offers a few unique properties. Most importantly, it offers control over where and when the assembly takes place. When chemical energy is continuously supplied, the assemblies are dynamic and can even be self-healing. Countless biological examples exist that use the conversion of chemical energy to regulate an assembly, e.g., the ATP-fueled assembly of actin or the Ca2+ ATPase, which also hydrolyzes ATP to pump Ca2+ across a membrane. If we want to create molecular assemblies as sophisticated as biology does, we should create analogs of molecular assemblies regulated through chemical reaction cycles.
A versatile, new reaction cycle to regulate self-assembly
Thus, my team set out to develop molecular assemblies that are regulated through chemical reaction cycles. First, we had to come up with a reaction cycle, i.e., a catalytic reaction cycle that converts a high-energy molecule (fuel) into a waste molecule of lower chemical potential and, while doing that, transiently activates a molecule. Such a reaction cycle needs to be versatile, so it can be widely applied. It needs to be scalable, so it can be used in materials. It needs to be a fast reaction cycle and should not suffer from any side reactions. Through design, we found one that fulfills all these requirements. We used the hydration of carbodiimide-based condensing agents to their corresponding ureas as the energy source for our chemical reaction. We catalyzed this reaction by using a dicarboxylate derivative as a precursor. In the activation reaction, the carbodiimide converts the precursor into its corresponding anhydride. That product, in water, has a short half-life of tens of seconds before it deactivates through hydrolysis, yielding the original precursor. In other words, at the expense of one molecule of carbodiimide, our precursor is transiently activated. The simplicity of the cycle is one of its strengths, i.e., it is easily applied to a wide variety of precursors and fuels without suffering from any side reactions.
Temporary materials
With a versatile chemical reaction cycle at hand, we designed precursors such that they are well soluble but assemble upon activation.2 The emerging assemblies and their properties are thus regulated through the kinetics of the chemical reaction cycle of activation and deactivation. For example, we designed peptides that were well-soluble and assembled into fibers that form hydrogels upon activation. Upon application of fuel, a gel would emerge that collapsed as soon as all fuel was depleted. In other words, we can now regulate the lifetime of the emerging material. Indeed, the more fuel added, the long material remained alive. We tested these concepts on self-erasing labels that would, for example, show when a product has expired,3 temporary nano-reactors that catalyze a reaction for a finite time,4 and emulsions that deliver hydrophobic drugs over their programmable lifetime.5
References
1. M. Tena-Solsona, B. Rieß, R. K. Grötsch, F. C. Löhrer, C. Wanzke, B. Käsdorf, A. R. Bausch, P. Müller-Buschbaum, O. Lieleg, J. Boekhoven, Nature Communications 2017, 8, 15895.
2. B. Rieß, R. K. Grötsch, J. Boekhoven, Chem 2019, 6, 527.
3. P. S. Schwarz, L. Tebcharani, J. E. Heger, P. Müller-Buschbaum, J. Boekhoven, Chem. Sci. 2021, 12, 9969–9976.
4. M. A. Würbser, P. S. Schwarz, J. Heckel, A. M. Bergmann, A. Walther, J. Boekhoven, ChemSystemsChem 2021, syst.202100015.
5. C. Wanzke, M. Tena-Solsona, B. Rieß, L. Tebcharani, J. Boekhoven, Mater. Horiz. 2020, 7, 1397–1403