Cracking the chiral code of DNA binding

Posted on 17 May 2018

MSc student Kiri Thornalley, working in the research team of Professor David Smith, has gained a detailed understanding of how self-assembled nanosystems bind biomolecules such as DNA.

For several years, the research group of Professor David Smith has been interested in binding DNA, because systems that can bind and transport DNA across cell membranes have potential applications in gene therapy. The Smith group’s synthetic systems typically self-assemble into nanostructures with positively charged surfaces in order to bind the negatively charged backbone of DNA.

However, in the bloodstream, other negatively charged molecules can also bind to such gene carriers and hence limit their activity. One such negatively charged biomolecule is heparin, which is very highly charged and can significantly disrupt DNA binding.

The Smith group made subtle structural changes to their synthetic DNA binders and explored how this affected the binding of both DNA and heparin. In particular, the researchers varied the three-dimensional ‘chirality’ of their synthetic systems.

They found that DNA preferred to bind to systems that display ‘right-handed’ lysine ligands on their surfaces. For heparin, no particular ligand preference was observed but it bound best if both chiral centres had the same ‘handedness’. 

In collaboration with the team of Professor Sabrina Pricl at University of Trieste, they gained more detailed understanding of how this selectivity results from structural differences between DNA and heparin – DNA is rigid and shape persistent, while heparin is adaptive and flexible. As such, they have quite different binding preferences.

Professor Smith noted: ‘By tuning the chirality of our nanoscale binders we can significantly alter the selectivity of their system, making a DNA binder much more resistant to the presence of heparin. Future work will therefore aim to use the understanding gained in this fundamental study to develop systems that are better optimised for specific medicinal applications, such as gene delivery.’

MSc student Kiri Thornalley said: ‘Being given so much independence to ensure all the different parts of this project came together, as well as being able to collaborate with Professor Pricl and her group at University of Trieste to gain greater insight into the thermodynamics of binding, has been really enjoyable.’

This research paper was dedicated to the retirement of Professor Francois Diederich, in whose research team Professor David Smith carried out his postdoctoral research fellowship 20 years ago.

The research is published in Angewandte Chemie.