Revealing the detail in four-stranded i-motif DNA structures

Project ID: 2228cd1337 (You will need this ID for your application)

Lead Supervisor: Zoё Waller

Project Summary:

DNA is often assumed to be a double helix, the “twisted ladder” structure first proposed by Watson and Crick in 1953. However, DNA can adopt different shapes, and these can be used as switches to control how it works.

DNA is comprised of four bases: adenine, guanine, thymine and cytosine. These are often described as the “building blocks” for life because they encode genetic information. DNA sequences which contain lots of cytosine can form alternative secondary structures which instead of being “twisted ladder” of two strands, are a very tightly packed “knot” of four strands of DNA. We call these structures i-motifs. Sequences of this type have been used as structural switches in nanotechnology but are also widespread throughout the human genome, shown to: exist in cells, play a role in gene expression and defining how long cells live. Despite these recent advances, we lack details about the exact nature of i-motif structures and targeting them with small molecule ligands. This is holding back drug discovery against these important biological targets. This project aims to use physical sciences approaches to reveal and understand more about the structures of biologically (and medically) relevant i-motif forming sequences. This will provide structural information that can be used for designing new drugs using rational-based drug design. We will combine X-ray crystallography, which will provide static structural information, with biophysical and cutting-edge computational methods, to provide insights into the dynamics; using known i-motif binding compounds/cations will also assist us in our work. Together, this will enable us to identify sites for drug design and development of new compounds as diagnostics and treatments for genetic diseases.

The project will provide new tools to investigate i-motif and other under-researched DNA structures and pipelines to compound leads for develop as treatments and diagnostics for genetic diseases.