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Artificial Molecular Machines for Synthesis
[Thesis]. Manchester, UK: The University of Manchester; 2015.
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Abstract
AbstractThe University of Manchester Sonja KuschelArtificial Molecular Machines for Synthesis18/06/2015In Nature sophisticated molecular machines are responsible for the synthesis of essential biomolecules and natural biopolymers. Inspired by these natural prototypes, scientist have begun to developed artificial systems that are able to perform complex synthetic tasks. Selected state-of-the-art examples, are presented and categorised according to their synthetic function: systems, which can distinguish between substrates and can also be regulated to produce different products, systems that selectively conduct multistep cascade reactions in mixtures of different reactants and systems that operate in a processive and sequence-specific fashion (Introduction).Following these examples, inspired by the ribosome, the synthesis and operation of the first artificial small-molecule machines based on a rotaxane structure capable of performing sequence-specific synthesis of a tri- and tetrapeptide from a molecular template is described. These machines operate through native chemical ligation (NCL), using a macrocyclic cysteine catalyst that iteratively removes proteinogenic amino acids from the strand and transfers them to a peptide elongation site. Successful operation on small scale generated milligram quantities of the peptides with a single sequence, determined by tandem mass spectrometry, corresponding to the original order of the amino acid building blocks on the strand (Chapter 1). Based on these first prototypes the system was extended to molecular machines operating on polymeric tracks. In this context the limits of the NCL mechanism were explored and the concept of the machine operation was investigated on a model system containing a polystyrene backbone with multiple leucine units. Here, machines with an average number of up to five L-leucyl groups were successfully operated. These initial studies represent the groundwork for the operation on longer polymeric systems containing sequences of amino acids (Chapter 2). Machines operating through a native chemical ligation (NCL) mechanism are restricted by a number of limitations: the rate of the reaction, the length and structure of the synthesised peptide, the cleavage of the product and finally the fact that peptide synthesis occurs in a reversed fashion to ribosomal synthesis (from C to N terminus). To overcome those limitations the development towards a 2nd generation molecular machine based on a transacylation catalyst was envisioned. Since this type of catalyst operates via a series of transacylation steps, the size of the transition state is kept the same throughout the operation, allowing access to longer peptides with fewer structural restrictions. Model systems using a thiophenol catalyst and a 1,2,4-triazol catalyst have been investigated (Chapter 3).