Dynamic covalent chemistry (DCC) has proven to be a valuable tool in creating fascinating molecules, structures, and emergent properties in fully synthetic systems. Here we report a system that uses two dynamic covalent bonds in tandem, namely disulfides and hydrazones, for the formation of hydrogels containing biologically relevant ligands. The reversibility of disulfide bonds allows fiber formation upon oxidation of dithiol‐peptide building block, while the reaction between NH−NH₂ functionalized C‐terminus and aldehyde cross‐linkers results in a gel. The same bond‐forming reaction was exploited for the “decoration” of the supramolecular assemblies by cell‐adhesion‐promoting sequences (RGD and LDV). Fast triggered gelation, cytocompatibility and ability to “on‐demand” chemically customize fibrillar scaffold offer potential for applying these systems as a bioactive platform for cell culture and tissue engineering.

Recently, the first self-replicating molecules have been described that are capable of catalyzing different reactions in addition to their own formation. These findings raise the question whether such catalytic promiscuity is a widespread characteristic, or whether it is feature restricted to a special subset of replicators. Another related issue is whether catalytic activity of these systems is sensitive to alterations in the peptide structure. Both of these questions are relevant in the context of evolution. Widespread catalytic promiscuity would be beneficial if replicators are to acquire a metabolism that involves catalysis of different chemical reactions. Furthermore, in order to enable adaptation and acquisition of new traits through mutation and selection, it is desirable that self-replicating molecules can mutate and explore structure space while retaining their catalytic activity. Here we demonstrate that catalytic promiscuity of a class of peptide based self-replicators is indeed a recurrent trait in a significant fraction of the probed structure space. Specifically, we investigated eighteen self-assembly driven self-replicators, each made from a different single building block, and six replicators that emerged from a binary building block mixture. Most of these were found to catalyze both the retro-aldol reaction of methodol, as well as the cleavage of fluorenylmethoxycarbonyl (FMOC) groups. No obvious correlation exists between the efficiencies with which replicators catalyze these two reactions, indicating that the reactions have different requirements with respect to catalyst structure. The degree of catalytic activity varied with replicator structure spanning up to three orders of magnitude. Of the binary mixtures, most gave replicators with activities in between those of the replicators made of the corresponding individual building blocks. However, in one instance, where specific interactions promote the formation of a specific two-building-block replicator mutant, this species had an activity that exceeded that of the corresponding single-building-block replicators. These observations imply that evolutionary enhancement of a specific catalytic activity of self-replicating molecules should be possible also in a regime where mutation rates are relatively high.

Dynamic covalent chemistry (DCC) has proven to be a valuable tool in creating fascinating molecules, structures, and emergent properties in fully synthetic systems. Here we report a system that uses two dynamic covalent bonds in tandem, namely disulfides and hydrazones, for the formation of hydrogels containing biologically relevant ligands. The reversibility of disulfide bonds allows fiber formation upon oxidation of dithiol‐peptide building block, while the reaction between NH−NH₂ functionalized C‐terminus and aldehyde cross‐linkers results in a gel. The same bond‐forming reaction was exploited for the “decoration” of the supramolecular assemblies by cell‐adhesion‐promoting sequences (RGD and LDV). Fast triggered gelation, cytocompatibility and ability to “on‐demand” chemically customize fibrillar scaffold offer potential for applying these systems as a bioactive platform for cell culture and tissue engineering.