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Abstract
Multiple G‐tracts within the promoter region of the c‐myc oncogene may fold into various G‐quadruplexes with the recruitment of different tracts and guanosine residues for the G‐core assembly. Thermodynamic profiles for the folding of wild‐type and representative truncated as well as mutated sequences were extracted by comprehensive DSC experiments. The unique G‐quadruplex involving consecutive G‐tracts II–V with formation of two one‐nucleotide and one central two‐nucleotide propeller loop, previously proposed to be the biologically most relevant species, was found to be the most stable fold in terms of its Gibbs free energy of formation at ambient temperatures. Its stability derives from its short propeller loops but also from the favorable type of loop residues. Whereas quadruplex folds with long propeller loops are significantly disfavored, a snap‐back loop structure formed by incorporating a 3’‐terminal guanosine into the empty position of a tetrad seems highly competitive based on its thermodynamic stability. However, its destabilization by extending the 3’‐terminus questions the significance of such a species under in vivo conditions.
Abstract
A DNA G‐quadruplex adopting a (3+1) hybrid structure was modified in two adjacent syn positions of the antiparallel strand with anti‐favoring 2′‐deoxy‐2′‐fluoro‐riboguanosine (FrG) analogues. The two substitutions promoted a structural rearrangement to a topology with the 5′‐terminal G residue located in the central tetrad and the two modified residues linked by a V‐shaped zero‐nucleotide loop. Strikingly, whereas a sugar pucker in the preferred north domain is found for both modified nucleotides, the FrG analogue preceding the V‐loop is forced to adopt the unfavored syn conformation in the new quadruplex fold. Apparently, a preferred C3′‐endo sugar pucker within the V‐loop architecture outweighs the propensity of the FrG analogue to adopt an anti glycosidic conformation. Refolding into a V‐loop topology is likewise observed for a sequence modified at corresponding positions with two riboguanosine substitutions. In contrast, 2′‐F‐arabinoguanosine analogues with their favored south‐east sugar conformation do not support formation of the V‐loop topology. Examination of known G‐quadruplexes with a V‐shaped loop highlights the critical role of the sugar conformation for this distinct structural motif.