Molecular self-assembly is the process by which molecules organize into superstructures through non-covalent interactions. Over the past decades, supramolecular chemistry has advanced to the point where Gigadalton assemblies can be constructed with near-atomic precision, with applications ranging from advanced materials to the liquid crystals in everyday displays.
Yet, compared to biology, our achievements remain modest. Cells use the same fundamental interactions, but with a vastly more diverse set of building blocks and a crucial additional principle: energy-driven regulation. While molecular self-assembly provides structure, chemical reactions impose dynamics. In biology, covalent modification—such as phosphorylation, redox changes, or nucleotide hydrolysis—continuously regulates when and where assemblies form.
A classic example is the GTP-driven assembly of tubulin into microtubules. Tubulin requires GTP binding to assemble, but once incorporated, neighboring units hydrolyze GTP to GDP, triggering disassembly. This coupling of self-assembly to a reaction cycle renders the process transient, energy-dependent, and highly controllable. Such regulation allows assemblies to be spatially and temporally precise, self-healing, and adaptive.
To approach the sophistication of biology, synthetic chemistry must go beyond static assemblies and develop chemically fueled self-assemblies—structures whose formation and dynamics are controlled by reaction cycles, just as in living systems.
A versatile, new reaction cycle to regulate self-assembly
Thus, our team set out to design molecular assemblies regulated by chemical reaction cycles. Such a cycle must convert a high-energy fuel into waste while transiently activating a precursor, and it must be versatile, scalable, fast, and free from undesirable side reactions.
We achieved this with the carbodiimide hydration cycle. In this system, a carbodiimide fuel activates a dicarboxylate precursor by converting it into its anhydride. The anhydride is short-lived in water, hydrolyzing back to the precursor within seconds, while the carbodiimide is consumed and transformed into a urea by-product. In effect, each fuel molecule transiently activates the precursor.
The elegance of this cycle lies in its simplicity and generality: it can be readily applied to diverse precursors and fuels, enabling robust and widely useful chemically fueled self-assembly.
Temporary materials
With a versatile chemical reaction cycle in hand, we designed precursors that remain soluble until activated, at which point they assemble into higher-order structures. The properties and lifetimes of these assemblies are dictated by the kinetics of the activation–deactivation cycle.
For instance, we created peptides that dissolve in water but, upon activation, assemble into fibers forming hydrogels. When fuel is supplied, a gel emerges; once the fuel is exhausted, the gel disassembles. Thus, the material’s lifetime becomes programmable—longer with more fuel.
This principle enables applications such as self-erasing labels that indicate product expiration, temporary nanoreactors that catalyze reactions for defined periods, and emulsions that release drugs over controlled lifetimes..
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Template-based information transfer in chemically fueled dynamic combinatorial libraries
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Regulating DNA-Hybridization Using a Chemically Fueled Reaction Cycle, J. Am. Chem. Soc. (pdf)