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Structural studies of DNA G-quadruplexes and ligand complexes

Hazel, Pascale; (2006) Structural studies of DNA G-quadruplexes and ligand complexes. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

G-quadruplexes can form a wide variety of structures, depending, amongst others, on the number and length of the G repeats, the length and composition of the loops, and the cations binding within the central channel. Several X-ray and NMR structures of G-quadruplexes have been determined, however there are still no guidelines which enable the structure of a G-quadruplex to be determined from its sequence. A combination of X-ray crystallography and molecular modelling has been used to obtain more insight into this problem. Due to the large number of factors involved in quadruplex folding, this study was limited to the influence of loop length and composition. The crystal structures of (G4T3G4)2 and (G4T2AG4)2 have been determined. Both sequences form antiparallel quadruplexes with lateral loops. Moreover, (G4BrUT2G4)2 formed two different antiparallel structures, a head-to-tail and a head-to-head dimer within the same crystal, suggesting that these are very similar in energy. Prior to crystallisation, structure prediction was undertaken using molecular dynamics simulations. Although both lateral and diagonal T3 and T2A loops were equally possible, shorter T2 loops restricted the quadruplex structures likely to form in solution. Molecular dynamics simulations using AG3T2AG3T2AG3T2AG3 X-ray and NMR structures as templates were able to show further effects of loop length on quadruplex folding. T and T2 loops could form only parallel or lateral loops, however this was dependent on the length of all loops in the quadruplex. Longer loops could form equally stable parallel and antiparallel structures. Simulations of ligand-quadruplex complexes were dependent on the initial structure of the quadruplex, emphasising the importance of quadruplex structure knowledge for ligand design. The combination of experimental and theoretical techniques has provided further insight into quadruplex structure, and has enabled the beginning of guidelines for quadruplex folding to be established.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Structural studies of DNA G-quadruplexes and ligand complexes
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; DNA; G-quadruplexes; Ligand; Quadruplexes
URI: https://discovery.ucl.ac.uk/id/eprint/10119463
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