Periodic Reporting for period 2 - InfoMols (Recognition-encoded synthetic information molecules)
Período documentado: 2023-04-01 hasta 2024-09-30
Linear oligomers encoded with a sequence of side-chains that have specific recognition properties are the basis for a range of properties that are the hallmarks of Nature’s nanotechnology: folding, substrate recognition, catalysis, self-assembly, and molecular replication. Nucleic acids are currently unrivalled as the only molecular architecture that embodies all of these properties, and this ability to encode, express and replicate sequence information is the molecular basis for the evolution of life on Earth. The aim of this project is to develop synthetic oligomeric molecules that encode and express chemical information in the same way as nucleic acids, via a sequence of recognition sites attached as side-chains to a linear backbone. We have already reported a range of synthetic oligomers that bear no relation to the structures of their biological counterparts, yet show efficient sequence-selective duplex formation via H-bonding interactions and can be used for replication of sequence information via covalent base-pairing interactions. Here we use hybrid systems that combine the most successful elements of backbone architecture and oligomerisation chemistry with a mixture of dynamic and kinetically inert base-pairing side-chains to obtain new synthetic systems that show all of the functional properties found in biomolecules. The ability to replicate sequence in recognition-encoded synthetic information molecules will enable exploration of new chemical spaces using directed evolution. These new chemical systems will allow us to evolve synthetic oligomers that fold into stable well-defined 3D structures, bind substrates with high affinity, and catalyse reactions. Programmable abiotic molecular nanotechnology will open a new area of chemistry with huge unexplored potential.
Conventional polymer materials are made from a single monomer unit that is assembled into polymeric chains in a single reaction step. For polymers made from more than one type of monomer, control over the sequence of building blocks incorporated into the chain requires a different approach. Sequence is defined by adding monomer units one at a time to the growing polymer chain in a multistep process. We have developed a highly efficient automated process to achieve this for a new class of synthetic polymers based on a melamine backbone using commercial equipment originally developed for peptide synthesis.
Several different types of monomer have been developed, all of which feature the same reactive groups, so that they can be used interchangeably in the synthesis of polymer chains with different side-chain sequences. We have shown that these polymers assemble into duplexes with excellent sequence-selectivity using a base-pairing system that pairs phosphine oxide and phenol side-chains via H-bonding interactions. The characterisation of these new types of macromolecular assembly represents a major challenge in the field, and we have developed a number of different techniques to achieve this. We have found covalent trapping using click chemistry to provide an excellent tool for identifying self-assembled complexes formed by the new melamine sequence polymers.
Biological sequence polymers, proteins and nucleic acids, are synthesised using template chemistry that allows sequence information to be copied from one chain to another. We have developed related approaches that will allow template synthesis and replication of synthetic sequence polymers. In addition to H-bonded base-pairs to control the sequence of incorporation of monomers into a growing copy chain, we have shown that an excellent degree of control can be achieved by using much stronger covalent base-pairing interactions in conjunction with H-bonding. Although only short sequences have been copied to date, the approach should scale well with polymer length.
Several different types of monomer have been developed, all of which feature the same reactive groups, so that they can be used interchangeably in the synthesis of polymer chains with different side-chain sequences. We have shown that these polymers assemble into duplexes with excellent sequence-selectivity using a base-pairing system that pairs phosphine oxide and phenol side-chains via H-bonding interactions. The characterisation of these new types of macromolecular assembly represents a major challenge in the field, and we have developed a number of different techniques to achieve this. We have found covalent trapping using click chemistry to provide an excellent tool for identifying self-assembled complexes formed by the new melamine sequence polymers.
Biological sequence polymers, proteins and nucleic acids, are synthesised using template chemistry that allows sequence information to be copied from one chain to another. We have developed related approaches that will allow template synthesis and replication of synthetic sequence polymers. In addition to H-bonded base-pairs to control the sequence of incorporation of monomers into a growing copy chain, we have shown that an excellent degree of control can be achieved by using much stronger covalent base-pairing interactions in conjunction with H-bonding. Although only short sequences have been copied to date, the approach should scale well with polymer length.
The progress to date puts us in a position to obtain polymers of any desired sequence in a routine manner. We have shown that these systems form sequence-selective duplexes and can be replicated in the same way as nucleic acids. The stage is now set to investigate the functional properties of these new polymers. Sequence polymers that form duplexes and exhibit sequence-dependent function, for example substrate binding or catalysis, will form a platform for the use of selection and evolution techniques to discover new functional materials, an approach that is currently only possible with biological molecules.