Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.737994
Title: Rational design, self-assembly and characterization of Guanine quadruplexes
Author: Dvorkin, Scarlett Anne
ISNI:       0000 0004 7226 2157
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2016
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Abstract:
The quadruplex formalism describes structural features of unimolecular quadruplex topologies having three loops, described herein as archetypal quadruplexes. The work described here provides a further development of the formalism, based on experimental and conceptual work. Dihedral angles of clockwise and anticlockwise propeller loops were analyzed and found to adopt comparable angles. These loops were also used to define limitations of propeller loop progression, reducing theoretically feasible topologies to 14. Glycosidic bond angle (GBA) conformations throughout the stem for 2, 3-, and 4-stacked versions of each of these 14 topologies have been detailed. Control elements of quadruplex structure have been established, including cation selection, loop length, and loop length relationship to number of stacking tetrads in quadruplex stem. A method to control the design of archetypal G-quadruplexes is proposed, based on rules of precedence. Four atomistic detail solution structures have been derived and structural models deposited in the Protein Data Base: 5J6U, 5J05, 5J4P, 5J4W. Aromatic protons of guanines protruding into grooves of quadruplex structures were evaluated by chemical shift to generate a method of chemical shift indexing. Although currently of limited use, it allows key inferences to be made before sequence-specific assignment of NMR signals, enabling a rapid decision to be reached regarding whether to pursue full structure determination. Investigation of the near-UV region of CD spectropolarimetry enabled derivation of a qualitative method to assess the number of stacking tetrads for two types of stem, representing an improvement on the current CD fingerprint approach to characterize three types of quadruplex stem. Significant steps in deriving the formalism have been made, which describe and predict structural elements of archetypal quadruplexes. These advances represent a major development in understanding of control of G-quadruplex folding. However, they are only one contribution to the advances needed for complete reproducible control of all quadruplex topologies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.737994  DOI: Not available
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