Design and Implementation of a Highly Selective Minimal Self‐Replicating System

Abstract

The development and deployment of self-replicating [1] molecular architectures [2] can potentially revolutionize the fabrication of materials on the nanometer scale. The emergence of protocols based on molecular replication will deliver synthetic machinery [3] that is capable of directing its own synthesis and cooperating with other similar systems to create an organized hierarchy. Within this broad objective, the development of efficient protocols that allow selfreplication, self-organization, and evolution [4] within synthetic supramolecular assemblies is essential. This approach to predetermined dynamic behavior has been termed "systems chemistry" by von Kiedrowski and co-workers.[5] Ultimately, we wish to exploit replicating systems in the construction, selection, [6] and amplification [7] of large molecular and supramolecular assemblies.The minimal self-replicator model [8] (Figure 1) provides the framework for our studies. Paul and Joyce highlighted [9] three parameters within this model that must be optimized to ensure an efficient system: minimization of product inhibition arising from a stable T·T complex; the suppression of the reaction [10] through A·B to form T inactive , which is inert catalytically; and the catalytic efficiency within the key ternary complex A·B·T. Under ideal conditions, template T presents its recognition sites in the correct orientation, assembles A and B, and then connects these two molecules to form an exact copy of itself by transmitting structural information to the forming template. This process completes an autocatalytic cycle. It is useful to recognize that, unlike traditional catalysts, there is no requirement for T to achieve particularly high turnover numbers as the inherently nonlinear kinetics should achieve amplification of the template once autocatalysis has become established. Additionally, as long as the duplex T·T is not excessively stable, propagation of the template T is exponential. Despite concerted efforts, there are relatively few reports of synthetic self-replicating systems. [5,11] In the context of our long-term goals, we must demonstrate that it is possible to exploit replication to amplify a single structure from a mixture based on its ability to guide its own formation through recognition processes, even when inherently unselective chemical reactions are used to covalently link the building blocks together. The reaction between an N-aryl nitrone and a maleimide is suitable for incorporation in a modular self-replicating system. The reaction proceeds readily at room temperature, and the rate and diastereoselectivity are almost immune to electronic substituent effects and adventitious catalysis by Brønsted acids. The two products (endo and exo) provide the means of exposing the efficiency of information transfer in any replicating system as the reaction is metronomic: the endo/exo ratio is always close to 3:1 in the absence of effects that arise from molecular recognition. Previous studies by us [12] demonstrated that this reaction can be incorporated...

Systems Chemistry: Logic Gates, Arithmetic Units, and Network Motifs in Small Networks

“…Over the years chemists have designed and characterized minimal self-replication systems made of nucleic acids (DNA [17][18][19][20] and RNA [21] ), peptides, [22][23][24][25] mixed protein-nucleic acids, [26] and small organic molecules. [27][28][29][30] The catalytic principles of Abstract: A mixture of molecules can be regarded as a network if all the molecular components participate in some kind of interaction with other molecules-either physical or functional interactions. Template-assisted ligation reactions that direct replication processes can serve as the functional elements that connect two members of a chemical network.…”

Templated Self‐Replication in Biomimetic Systems

“…[24] Similarly, Wang and Sutherland developed an organic chemical replicator based on the Diels-Alder reaction in which the product efficiently catalyzes its own formation from an ene and diene. [26][27][28] DCLs allow the generation of novel molecules formed by reversible reactions of simple building blocks under thermodynamic control. Using Diels-Alder and 1,3-dipolar cycloaddition chemistry, Philp and co-workers both designed and selected self-complementary replicators from dynamic combinatorial libraries (DCLs).…”

“…[25] In both cases, the specificity that leads to self-replication is derived from specific and complementary hydrogen bonding and aromatic stacking interactions between product and substrate ( Figure 2a). [29,30] Intriguingly, some of the DCL-derived replicators display self-amplification in heterogeneous reaction mixtures [27] or complex and environmentally responsive chemical replication networks with cross-catalytic reaction pathways. [26][27][28] DCLs allow the generation of novel molecules formed by reversible reactions of simple building blocks under thermodynamic control.…”

Complex Self‐Sorting Systems

“…51,52,[74][75][76] Systems chemists study complex multicomponent systems that exhibit emergent properties that go beyond those of their components. Some systems chemists take their inspiration from biology and design systems that exhibit properties such as selfreplication, [77][78][79][80][81][82][83] whereas others add new components to existing biological systems in an attempt to control biological function. Other systems chemists take inspiration from technology and aim to integrate individual molecular devices into more complex molecular machines.…”