Biomimetic control systems from artificial components

The beneficial interaction of artificial biomimetic structures with living systems forms the basis of medicinal chemistry and chemical biology at the molecular level, and of bioengineering at the tissue or organism level. The main target of this proposal is to explore the potential for such interactions at the nano-scale, devising artificial analogues of the components of biological control systems that communicate, amplify and manipulate information to induce control over chemical and biochemical reactivity and pathways. Clayden and his co-workers have shown recently that oligomers of the achiral quaternary amino acid Aib, which form stable, well-defined 310 helical foldamer structures, are able to mimic some of the properties and functions of biological receptors such as the GPCR. They showed that a stereochemical influence at one end of an otherwise achiral helix is capable of inducing a screw-sense preference that extends over numerous helical turns. They used this knowledge to devise switchable structures in which absolute configuration at a stereogenic centre at one end of a helix is able to induce a change in the environment of a spectroscopic reporter at the other end, demonstrating for the first time that screw-sense preference in an otherwise achiral helix is able to communicate information over multi-nanometer distances. In addition, they were able to induce switching via reversible covalent interactions in a process that mimics the binding of a ligand at a binding site, with consequent induction of conformational change in a receptor. Thus, seminal progress towards competent biomimetic systems displaying some of the functions of biological molecular communication devices has been made. However, so far the communication has been limited to single molecules: the communication has been intramolecular. Therefore, the next key breakthrough to be addressed in this proposal will be the development of methods for communicating information between molecules, in an intermolecular manner, ideally leading to a chemical output of information, for example a change in reactivity or the release of a chemical messenger. This challenge shall be addressed by two parallel approaches. In the first, we shall aim for direct intermolecular communication between relatively unfunctionalised helical molecules, in a non-hydrogen-bonding solvent. These studies will probe some fundamental properties of the helices in question, but it is likely that we will need to induce tighter interactions between the helices. In parallel, therefore, we will explore the potential for intermolecular communication even in hydroxylic solvents and ultimately in water. The end target of this project would represent a major breakthrough in the synthetic construction of biomimetic control systems, adding conformational and stereochemical aspects to concepts in systems chemistry and even synthetic biology.

The main breakthrough achieved in the course of my fellowship was the development and investigation of methods for intermolecular communication between helical molecules via chiral anion recognition involving hydrogen bonding by combining the properties of foldamers and ureas. These non-covalent interactions alter in different solvents and were found to be important in controlling the flow of information through the helical domain. Anion recognition chemistry has emerged as an exciting research field in recent years owing to the biological and environmental relevance of anions. Urea compounds have a leading role in this field as they possess structural features including their ability to function as hydrogen-bond donors. In nature, binding of a ligand to a protein receptor leads to local reorganisation of the structure of the protein and can be classified as a conformational change. The transduction of biological signals depends on the communication of this conformational change. First, we have to make clear what 'information' means in chemical structures. Stereochemistry, the information that we are looking at, describes the shape of a molecule, in a way as we would e.g. describe the shape of our hands. Simplified, it can be viewed as a form of binary information: M and P are the only alternative forms of a helix (in the same way that our left and right hand look the same but a glove for the right hand can't be put on the left hands as they are mirror images of each other). As in nature, we can achieve transduction of signals in synthetic structures by foldamers, extended molecules with well-defined conformational properties. This project built on the synthesis and transformation of helical oligomers made up of the achiral aminoisobutyric acid (Aib) that forms stable, well-defined foldamer structures. As other helical foldamers built of achiral subunits, peptides of Aib exist as two rapidly interconverting helices (no preference for (M) and (P) helix at room temperature). We could use the comparison of a pair of socks: a single sock will fit either foot. An external chiral input (this contains the information we want to transfer) that interacts with the urea binding site of our Aib foldamer is able to perturb the equilibrium between M and P, inducing a conformational preference. Now, the existence of one helix is favoured over the other and we can quantify the degree of this preference that is relayed through the foldamer by 'reading' an output at the other end of the chain.A multi-functional anion recognition binding site has been developed and was successfully applied for synthetic signal transduction. The insights gained in this project contribute significantly to the understanding of the construction of synthetic biomimetic control systems, by adding conformational and stereochemical aspects to concepts in systems chemistry and even synthetic biology.