完宖宑宄宆季孵孳孵孵
1 O- 05

Crystallographic studies of ruthenium polypyridyl complexes
bound to DNA G-quadruplexes: Towards design, specificity, andfunction
Kane McQuaid
Department of Chemistry, University of Reading, Whiteknights, Reading, RG6 6AH, UK.
Ruthenium polypyridyl complexes, along with offering a unique, modular approach to DNA
binder construction; can be tailored to present desirable photochemical and electrochemical
properties. As such, ruthenium based DNA intercalators possess the ability to serve many usefulfunctions, for instance, as site specific fluorescent DNA markers, electrochemical probes andphotoactivated base-specific oxidizers.1,2 More recently, the ability to target higher order DNA
secondary structures, such as G-quadruplexes, have been reported using modified metal
polypyridyls.3 Research directed at stabilising or damaging G-quadruplex DNA has increased
substantially of late as a result of the assemblies proven existence in the living cell.4 The formation or
dissolution of such assemblies has been linked to several topical disorders and biological processes,
such as the proliferation of cancers, telomere maintenance, and in the expression/suppression ofgenes.5 As such, G-quadruplexes have been heavily researched as an exciting biological target for thebinding of prospective small molecule drugs; whereby specifically binding and stabilising theseassemblies can be seen as a pathway for the therapeutic modulation of pertinent biologicalprocesses. Development of such compounds is however made difficult by the fact that relatively few
structural models detailing these binding modes are available (and are often difficult to acquire!).
Here we report how macromolecular X-ray
crystallography can be utilised, in tandem with
spectroscopic and biophysical techniques, in theelucidation of the DNA-binding properties of ruthenium
polypyridyl species. Specifically, we report the first
crystal structures of photoactive ruthenium complexes
binding to G-quadruplexes.6,7 Of particular note we will
present our most recent structure of a ruthenium
complex containing a chromophore with an extended πsurface bound to a unimolecular G-quadruplex.8 The
quadruplex in this case is a derivative of the telomericrepeat sequence, and interestingly this system folds into
an antiparallel chair-form quadruplex; the first of its kind
to be crystallised with a bound ligand.
5’-GGG-TTA-GGG-TTA-GGG-TTT-GGG-3’
In addition to crystallographic data, we report
how such stabilising interactions can affect theFigure – Crystal structure of a ruthenium
replication of quadruplex DNA by the action ofpolypyridyl complex bound to unimolecularpolymerases, and how these interactions affect the in G-quadruplex.
cellulo formation of quadruplex DNA; with particularfocus on enantiospecificity, photophysical damage, and π-extended chromophores. Using thesegained structural perspectives it is possible to suggest rationale for observed in vitro measurements,and allow for the superior design of ligands devised to target and selectively stabilize DNA secondarystructure.

完宖宑宄宆季孵孳孵孵REFERENCES
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McQuaid, K., Takahashi, S., Baumgaertner, L., Cardin, D.J., Paterson, N.G., Hall, J.P., Sugimoto, N., and Cardin,2021).
C.J. Ruthenium polypyridyl complex bound to a unimolecular chair-form G-quadruplex. Manuscript submitted, (2ACKNOWLEDGEMENTS
The author thanks colleagues at the University of Reading and Diamond Light Source Ltd (Profs andPhD candidates alike), especially Prof. Christine Cardin, Prof. David Cardin, and Dr James Hall, fortheir inputs, help, and wisdoms. The author would also like to say a massive thank you to Dr
Shuntaro Takahashi, Dr Hisae Tateishi-Karimata, Prof. Naoki Sugimoto and the lead researchers atFIBER for their continued collaborations, but also for hosting him in their institute in previous trips
to Japan. This work was supported by grants and funding from the BBSRC, JSPS, Diamond Light
Source, and the University of Reading.
BIOGRAPHY
Dr Kane McQuaid is a Postdoctoral Research Associate in thechemistry department at the University of Reading, UK. In 2020 Dr.
McQuaid completed his PhD in the same department under thesupervision of Professor Christine Cardin. His current area ofinterest is the study of ligand binding to G-quadruplexes, withparticular focus on using X-ray crystallography to aid in the designof DNA-binding photoactive metal complexes.

*Email: k.mcquaid@reading.ac.uk