Generating system-level responses from a network of simple synthetic replicators

The financial support for this work was provided by EaStCHEM and the Engineering and Physical Sciences Research Council (Grant EP/K503162/1).The creation of reaction networks capable of exhibiting responses that are properties of entire systems represents a significant challenge for the chemical sciences. The system- level behavior of a reaction network is linked intrinsically to its topology and the functional connections between its nodes. A simple network of chemical reactions constructed from four reagents, in which each reagent reacts with exactly two others, can exhibit up-regulation of two products even when only a single chemical reaction is addressed catalytically. We implement a system with this topology using two maleimides and two nitrones of different sizes—either short or long and each bearing complementary recognition sites—that react pairwise through 1,3-dipolar cycloaddition reactions to create a network of four length-segregated replicating templates. Comprehensive 1H NMR spectroscopy experiments unravel the network topology, confirming that, in isolation, three out of four templates self-replicate, with the shortest template exhibiting the highest efficiency. The strongest template effects within the network are the mutually cross-catalytic relationships between the two templates of intermediate size. The network topology is such that the addition of different preformed templates as instructions to a mixture of all starting materials elicits system-level behavior. Instruction with a single template up-regulates the formation of two templates in a predictable manner. These results demonstrate that the rules governing system-level behavior can be unraveled through the application of wholly synthetic networks with well-defined chemistries and interactions.PostprintPeer reviewe

Exponential self-replication enabled through a fibre elongation/breakage mechanism

Self-replicating molecules are likely to have played a central role in the origin of life. Most scenarios of Darwinian evolution at the molecular level require self-replicators capable of exponential growth, yet only very few exponential replicators have been reported to date and general design criteria for exponential replication are lacking. Here we show that a peptide-functionalized macrocyclic self-replicator exhibits exponential growth when subjected to mild agitation. The replicator self-assembles into elongated fibres of which the ends promote replication and fibre growth. Agitation results in breakage of the growing fibres, generating more fibre ends. Our data suggest a mechanism in which mechanical energy promotes the liberation of the replicator from the inactive self-assembled state, thereby overcoming self-inhibition that prevents the majority of self-replicating molecules developed to date from attaining exponential growth

Dynamic covalent chemistry in aid of peptide self-assembly

Self-assembled peptide systems have been widely studied in the context of gaining understanding of the rules that govern biomolecular processes and increasingly as new bio-inspired nanomaterials. Such materials may be designed to be highly dynamic, displaying adaptive and self-healing properties. This review focuses on recent approaches, which exploit reversible covalent and noncovalent chemistry in combination with peptide-based self-assembly. Selected examples of recent advances include sulphur and nitrogen-based reversible reactions, metal-ligand coordination and enzyme-assisted transamidation that lead to structures such as catenanes, nanofibres, beta-hairpins and coiled-coil assemblies. It is demonstrated that these structures give rise to nanomaterials with emergent properties that are highly sensitive and adaptive to external conditions and may allow for in vitro evolution of novel peptide nanostructures via templating or self-recognition

Locking an oxidation-sensitive dynamic peptide system in the gel state

We describe an enzyme-driven dynamic supramolecular peptide system which displays multiple reversible pathways, giving rise to emergent properties that are dictated by environmental conditions and that can be locked in a gel-state

Micelle to fibre biocatalytic supramolecular transformation of an aromatic peptide amphiphile

We use a range of spectroscopic methods to provide mechanistic insight into a phosphatase-driven supramolecular transformation whereby an amphiphilic peptide building block, upon dephosphorylation, switches from a solution-phase, micellar structure to a gel-phase, chiral uni-directional nanofibre morphology

Target-driven selection in a dynamic nitrone library

Nitrones undergo dynamic exchange in chloroform at room temperature through two mechanisms-hydrolysis and recombination or hydroxylamine addition/elimination, this dynamic exchange is harnessed to select a nitrone-based bis(amidopyridine) receptor for diacids from a group of four nitrones through its binding to a glutaric acid-based target.</p

Sequence/structure relationships in aromatic dipeptide hydrogels formed under thermodynamic control by enzyme-assisted self-assembly

Self-assembled supramolecular structures of peptide derivatives often reflect a kinetically trapped state rather than the thermodynamically most favoured structure, which presents a challenge when trying to elucidate the molecular design rules for these systems. In this article we use thermodynamically controlled self-assembly, driven by enzymatic condensation of amino acid derivatives, to elucidate chemical composition/nanostructure relationships for four closely related Fmoc-dipeptide-methyl esters which form hydrogels; SF, SL, TF and TL. We demonstrate that each of the four systems self-assemble to form extended arrays of beta-sheets which interlock via pi-stacking of Fmoc-moieties, yet with subtle differences in molecular organisation as supported by rheology, fluorescence emission spectroscopy, infrared spectroscopy, X-ray diffraction analysis and molecular mechanics minimisation

Diversification of self-replicating molecules

How new species emerge in nature is still incompletely understood and difficult to study directly. Self-replicating molecules provide a simple model that allows us to capture the fundamental processes that occur in species formation. We have been able to monitor in real time and at a molecular level the diversification of self-replicating molecules into two distinct sets that compete for two different building blocks ('food') and so capture an important aspect of the process by which species may arise. The results show that the second replicator set is a descendant of the first and that both sets are kinetic products that oppose the thermodynamic preference of the system. The sets occupy related but complementary food niches. As diversification into sets takes place on the timescale of weeks and can be investigated at the molecular level, this work opens up new opportunities for experimentally investigating the process through which species arise both in real time and with enhanced detail