Networks are the building blocks in the world around us, and the inherent interconnect- edness at their core often exerts an influence over our everyday lives that is challenging to predict. The all-pervasive presence of networks in nature is reflected in the number of disciplines increasingly involved in the study of complex systems, with properties that are beyond those exhibited by their individual components. The field of chemistry also experienced a paradigm shift around twenty years ago, moving away from the study of molecular matter in isolation and starting to embrace the notion of complexity and complex networks. The interdisciplinary research directed towards the construction and analysis of complex networks, known collectively as systems chemistry,43,63,66,182 brings together aspects of supramolecular chemistry, origins-of-life research and far- from-equilibrium systems, endeavouring to develop a better understanding of complex systems and phenomena, and the requirements leading to their emergence. Taking inspiration from the systems found in nature, in particular the complexity of living systems, systems chemistry employs the bottom-up approach to design, development and investigation of synthetic chemical systems as models for complex behaviour, with the view to examining the system-level properties that arise as a result of the interac- tions and reactions between the components within these networks. A phenomenon of particular interest to systems chemistry is self-replication—the complex process at the very core of living organisms.
Synthetic systems present a unique opportunity for systems chemists to study the complex phenomenon of self-replication using chemical networks constructed using molecules with well-defined structures and with catalytic and recognition properties that can be probed and characterised experimentally. The developments in the field of systems chemistry have, as illustrated by the examples presented in this introduction, produced a great variety of replicating systems based on oligonucleotides,79,82,83,85,87
peptides88,92,93,97,99,105and small synthetic molecules,109,114,115,120,127highlighting and
demonstrating40,67,69,70,183that the ability to replicate is not exclusive to complex biolog-
ical systems, exploiting a complex enzymatic machinery. In addition to self-replication, these systems were shown to express a number of properties that emerged as a conse- quence of the interactions embedded in the network—error-correction, stereo-specific replication and Boolean logic operations, to name a few. Peptide-based replicating
systems in particular, have achieved68,106,145,184,185a notable level of sophistication, ex-
amining networks comprising more than a single replicator—a feature significantly less well-developed in replicating systems exploiting oligonucleotides and small-organic molecules.
The requirements for the operation of self-replicating systems in isolation have been established. The processes in complex networks in the real world, however, never operate in isolation—nor do complex biological systems function using fully preformed components. Instead, components of biological networks achieve their formation from mixtures of precursors. The reaction environment is, in fact, a parameter that is only beginning to be explored in systems chemistry, where majority of replicating systems are examined under the well-established, closed system conditions (i.e. well-stirred batch reactor model). In this respect, the DCC approach presents134,178an extremely
useful tool for the construction of complex networks with an added component of a dynamically-exchanging pool of components—a reaction environment for the study of chemical networks that is one step closer to the dynamic, often heterogeneous environ- ment found in nature. Nevertheless, despite the significant progress in the coupling of kinetically-driven irreversible reaction processes to dynamic covalent systems, attempts at integrating self-replication processes with the DCC approach are only just starting to appear. More scarce yet, are experimental reports directed at investigating more than a single template-mediated processes under dynamic conditions—an environment for the examination of simultaneously operating replicating systems that can facilitate our understanding of the process and the requirements that allowed a replicating species to exploit a mixture of components for its own synthesis during the processes of chemical evolution.
The aim and direction of the work described in this thesis is to exploit the expertise developed over the years in the Philp laboratory in designing self-replicating systems, and explore networks of replicator based on small organic molecules—in particular, replicators connected by a requirement for a shared building block. Such networks of interconnected replicators present a model system for studying how the reaction and recognition-mediated processes govern the preference,i.e. the selectivity, for one replicator over another. Building on the study of a reaction network in isolation,i.e. in a closed reaction environment driven by kinetic selection, the behaviour of the net- work can be examined within a dynamic environment, constructed using the DCC approach—allowing determination of how the dynamic selection alters the outcome of the competition between replicators.
The work will exploit various algorithms for network resolutionc—i.e. the resulting
distribution of replicators competing for a shared building block will be determined by the type of reaction environment and the covalent and non-covalent selection processes employed. The study of replicating networks will be aided by computational modelling, kinetic fitting and kinetic simulations—tools intended to complement the experimental analysis and allow examination of the experimental systems under a range of conditions that might be challenging experimentally. Ultimately, it is envisaged that examination of different modes of selection in a replicating system, driven by either a change in the reaction environment or the presence of an additional recognition-mediated processes, will help build a more comprehensive picture of how the network of replicators behaves, its requirements and limitations.
Some of the work described inSection 1.5.3has been published in:
• T. Kosikova, H. Mackenzie and D. Philp, Chem. Eur. J. 2016, 22,
1831–1839
cTraditionally, resolution refers to a chemical process by which a racemic mixture is separated into the constituent enantiomers. In this thesis, the term resolution will be used to denote the process by which the reaction format, the covalent and non-covalent selection processes in a network of replicators determine the final product distribution.
CHAPTER 2
GENERAL DESIGN PRINCIPLES AND OBJECTIVES
2.1 Preamble
The examination of a network of replicators constructed from small organic molecules is unlikely to identify absolutely the precise steps in the route leading to the emergence of the first self-replicating molecule capable of sustaining itself from a mixture of chemical components on the prebiotic earth. Nevertheless, studying the phenomenon of self-replication with model chemical compounds can provide information about the behaviour of a replicating system, how it correlates with its structural features, and the interplay between the various recognition and reaction processes operating within the network. In this section, the general design principles and objectives pertaining to the replicating networks examined within this thesis are introduced, with particular focus on the reaction and recognition requirements necessary for successful operation of replicating systems, and the different modes of system resolution and reaction environment available for their analysis.