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Biological behaviour of metal-containing nucleic acids

Principal Supervisor: Professor James Tucker - School of Chemistry

Co-supervisor: Sarah Horswell - Chemistry, Timothy Dafforn - Biosciences

PhD project title: Biological behaviour of metal-containing nucleic acids

University of Registration: University of Birmingham

Project outline:

The project will involve the study of unnatural nucleic acids containing metals that have recently been developed in the School of Chemistry at the University of Birmingham. These vary from modified nucleic acids, in which DNA is tagged with redox-active metal complexes[1], to completely artificial nucleic acids,[2] in which the sugar-phosphate backbone of DNA is replaced entirely with metal-containing units, making ferrocene nucleic acid (or FcNA, see diagram below); these structures contain iron atoms that run along the nucleic acid backbone, giving them redox-activity as a result of the reversible Fe(II)-Fe(III) redox couple.

This project will focus on developing a fuller understanding of the properties of these new redox-active oligomers and their application in the field of biological nanotechnology. As potential forms of xeno nucleic acids (XNA),[3] they fall within the domain of synthetic biology and the drive to fabricate new unnatural structures that can mimic or even enhance the properties of natural systems.

Pic1

Directions for study will include examining enzyme activity (for example with helicases or polymerases), molecular modelling, electrochemistry and tagging to other biological components (e.g. bacteriophages[4]) for spectroscopic and electrochemical sensing applications.

One exciting prospect will be to examine whether these nucleic acids can be copied through their metal modification site and amplified in the PCR reaction. Similar approaches have already been used for other nucleic acids with backbone modifications that do not contain metals.[5]

References: 

  1. Duprey, JLHA; Carr-Smith, J; Horswell, SL; Kowalski, J; Tucker, JHR. “Macrocyclic Metal Complex–DNA Conjugates for Electrochemical Sensing of Single Nucleobase Changes in DNA”, J. Am. Chem. Soc., 2016, 138, 746-749
  2. H. V. Nguyen, Z.Y. Zhao, A. Sallustrau, S. L. Horswell, L. Male, A. Mulas and J. H. R. Tucker, “A Ferrocene Nucleic Acid oligomer as an organometallic structural mimic of DNA”, Chem. Commun., 2012, 48, 12165-12167
  3. Pinheiro, VB; Taylor, AI; Cozens, C; Abramov, M; Renders, M; Zhang, S; Chaput, JC; Wengel, J; Peak-Chew, S-Y; McLaughlin, SH; Herdewijn, P; Holliger, P. “Synthetic Genetic Polymers Capable of Heredity and Evolution”, Science, 2012, 336, 341-344
  4. Carr-Smith J, Pacheco-Gómez R, Little HA, Hicks MR, Sandhu S, Steinke N, Smith DJ, Rodger A, Goodchild SA, Lukaszewski RA, Tucker JHR, Dafforn TR. “Polymerase Chain Reaction on a Viral Nanoparticle”, ACS Synth. Biol. 2015, 4, 1316-1325.
  5. El-Sagheer AH; Brown, T. “Synthesis and Polymerase Chain Reaction Amplification of DNA Strands Containing an Unnatural Triazole Linkage” J. Am. Chem. Soc., 2009, 131, 3958.

BBSRC Strategic Research Priority: Industrial Biotechnology and Bioenergy

Techniques that will be undertaken during the project:

Students will receive training in DNA monomer (metal complex) synthesis and DNA synthesis, as well as various purification techniques, including HPLC. Biophysical techniques will include PCR, electrochemistry, gel electrophoresis, ultraviolet-visible and circular dichroism spectroscopy.

Contact: Professor James Tucker, University of Birmingham