Self-replicating molecules are likely to have played an important role in the origin of life, and a small number of fully synthetic self-replicators have already been described. Yet it remains an open question which factors most effectively bias the replication toward the far-from-equilibrium distributions characterizing even simple organisms. We report here two self-replicating peptide-derived macrocycles that emerge from a small dynamic combinatorial library and compete for a common feedstock. Replication is driven by nanostructure formation, resulting from the assembly of the peptides into fibers held together by beta sheets. Which of the two replicators becomes dominant is influenced by whether the sample is shaken or stirred. These results establish that mechanical forces can act as a selection pressure in the competition between replicators and can determine the outcome of a covalent synthesis.

Dynamic combinatorial chemistry [1] was originally conceived as a method for developing synthetic receptors and ligands for biomolecules. Dynamic combinatorial libraries (DCLs) are produced by linking building blocks together using a reversible reaction, resulting in a thermodynamically controlled product distribution. Addition of a guest or a biomolecule shifts the distribution to those library members that bind best to the external target; a process referred to as templating. Recently, the first examples have appeared of DCLs in which molecular recognition does not involve an externally added template, but takes place between library members.[2] Such self-templated DCLs constitute a promising approach for the development of new self-assembling materials. Self-assembly provides the driving force to shift the equilibrium in favor of the very molecules that self-assemble, so that these materials are in effect self-synthesizing. We now report that a selfassembled material produced by dynamic combinatorial chemistry can be further stabilized by rearranging the dynamic covalent disulfide bonds that were underlying the dynamic combinatorial process. We show how photoinitiated disulfide exchange converts fibrous stacks of macrocycles into polymeric products, enhancing the stability of the fibers and causing gelation of the aqueous solution.We recently reported how hexameric disulfide macrocycles emerge upon shaking a DCL made from dithiol 1 (Scheme 1).[2e] This building block is equipped with a short peptide sequence, predisposed to b-sheet formation by alternating hydrophobic and hydrophilic amino acid residues. While the peptide is too short to self-assemble on its own, the DCL made upon oxidizing dithiol 1 in aqueous solution contains a number of macrocycles of different ring sizes that display a different number of peptides. We reasoned that selfassembly becomes feasible for a critical size of the macrocycle that displays a sufficient number of peptides. Indeed, for a DCL made from 1 that is agitated by shaking, self-assembly of the hexameric macrocycles (1 6 ) occurs, resulting in the formation of fibers and shifting the product distribution in favor of the cyclic hexamer. The solution remains free flowing as the fibers are fragile and break when subjected to moderate shear forces.[2e]We have discovered that photoirradiation (three days, using an 8 W UV lamp, 365 nm) of a nonagitated solution containing hexamer fibers ([1 6 ] is around 0.6 mm) results in the formation of a hydrogel [3] (Figure 1 a). Oscillatory rheology [4] experiments showed that a relatively rigid gel is formed with a ratio between storage (G') and loss (G'') moduli of 12 at low oscillatory frequencies (see Figure S1 in the Supporting Information).Photoirradiation of disulfides can induce their homolytic cleavage [5] giving thiol radicals that can attack nearby disulfide bonds, resulting in disulfide exchange.[6] This underutilized radical-mediated exchange mechanism is different from the ionic (thiolate-anion-mediated) mechanism [7] that is ty...

Dynamic combinatorial chemistry [1] was originally conceived as a method for developing synthetic receptors and ligands for biomolecules. Dynamic combinatorial libraries (DCLs) are produced by linking building blocks together using a reversible reaction, resulting in a thermodynamically controlled product distribution. Addition of a guest or a biomolecule shifts the distribution to those library members that bind best to the external target; a process referred to as templating. Recently, the first examples have appeared of DCLs in which molecular recognition does not involve an externally added template, but takes place between library members. [2] Such self-templated DCLs constitute a promising approach for the development of new self-assembling materials. Self-assembly provides the driving force to shift the equilibrium in favor of the very molecules that self-assemble, so that these materials are in effect self-synthesizing. We now report that a selfassembled material produced by dynamic combinatorial chemistry can be further stabilized by rearranging the dynamic covalent disulfide bonds that were underlying the dynamic combinatorial process. We show how photoinitiated disulfide exchange converts fibrous stacks of macrocycles into polymeric products, enhancing the stability of the fibers and causing gelation of the aqueous solution.We recently reported how hexameric disulfide macrocycles emerge upon shaking a DCL made from dithiol 1 (Scheme 1). [2e] This building block is equipped with a short peptide sequence, predisposed to b-sheet formation by alternating hydrophobic and hydrophilic amino acid residues. While the peptide is too short to self-assemble on its own, the DCL made upon oxidizing dithiol 1 in aqueous solution contains a number of macrocycles of different ring sizes that display a different number of peptides. We reasoned that selfassembly becomes feasible for a critical size of the macrocycle that displays a sufficient number of peptides. Indeed, for a DCL made from 1 that is agitated by shaking, self-assembly of the hexameric macrocycles (1 6 ) occurs, resulting in the formation of fibers and shifting the product distribution in favor of the cyclic hexamer. The solution remains free flowing as the fibers are fragile and break when subjected to moderate shear forces. [2e] We have discovered that photoirradiation (three days, using an 8 W UV lamp, 365 nm) of a nonagitated solution containing hexamer fibers ([1 6 ] is around 0.6 mm) results in the formation of a hydrogel [3] (Figure 1 a). Oscillatory rheology [4] experiments showed that a relatively rigid gel is formed with a ratio between storage (G') and loss (G'') moduli of 12 at low oscillatory frequencies (see Figure S1 in the Supporting Information).Photoirradiation of disulfides can induce their homolytic cleavage [5] giving thiol radicals that can attack nearby disulfide bonds, resulting in disulfide exchange. [6] This underutilized radical-mediated exchange mechanism is different from the ionic (thiolate-anion-mediated) mechanism [7] t...