Structural properties of the [d(G3T4G3)]2 quadruplex: evidence for sequential syn-syn deoxyguanosines

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Abstract
Two-dimensional 1H NMR studies on the dimerlc hairpin quadruplex formed by d(G3T4G3) In the presence of either NaCI or KCI are presented. In the presence of either salt, the quadruplex structure Is characterized by half the guanlne nucleosldes In the syn conformation about the glycosldlc bond, the other half In the antl conformation, as reported for other similar sequences. However, ¹H NOESY and ¹H-31P heteronuclear correlation experiments demonstrate that the deoxyguanosines do not strictly alternate between syn and antl along Individual strands. Thus we find the following sequences with regard to glycosldlc bond conformation: 5'-G1SG2SG3AT4AT5A-T6AT7AG8SG9AG10A-3' and 5'-G11SG12AG13AT14AT15AT16AT17AG18SG19SG20A-3', where S and A denote syn and antl, respectively. This represents the first experimental evidence for a nucleic acid structure containing two sequential nucleosldes in the syn conformation. The stacking Interactions of the resulting quadruplex quartets and their component bases have been evaluated using unrestrained molecular dynamics calculations and energy component analysis. These calculations suggest that the sequential syn-syn/ antl - antl and syn - antl quartet stacks are almost equal in energy, whereas the antl-syn stack, which Is not present in our structure, is energetically less favorable by about 4 kcal/mol. Possible reasons for this energy difference and its implications for the stability of quadruplex structures are discussed.