A non-empirical chromophoric interpretation of CD spectra of DNA G-quadruplex structures

Abstract

G-quadruplex DNA (G4-DNA) structures are four-stranded helical DNA (or RNA) structures, comprising stacks of G-tetrads, which are the outcome of planar association of four guanines in a cyclic Hoogsteen hydrogen-bonding arrangement. In the last decade the number of publications where CD spectroscopy has been used to study G4-DNAs, is extremely high. However, with very few exceptions, these investigations use an empirical interpretation of CD spectra. In this interpretation two basic types of CD spectra have been associated to a single specific difference in the features of the strand folding, i.e. the relative orientation of the strands, "parallel" (all strands have the same 5' to 3' orientation) or "antiparallel". Different examples taken from the literature where the empirical interpretation is not followed or is meaningless are presented and discussed. Furthermore, the case of quadruplexes formed by monomeric guanosine derivatives, where there is no strand connecting the adjacent quartets and the definition parallel/antiparallel strands cannot apply, will be discussed. The different spectral features observed for different G-quadruplexes is rationalised in terms of chromophores responsible for the electronic transitions. A simplified exciton coupling approach or more refined QM calculations allow to interpret the different CD features in terms of different stacking orientation (head-to-tail, head-to-head, tail-to-tail) between adjacent G-quartets irrespectively of the relative orientation of the stands (parallel/antiparallel).

Inhibition of Cancer Cell Migration and Invasion through Suppressing the Wnt1-mediating Signal Pathway by G-quadruplex Structure Stabilizers

“…CD provides spectral information for the existence of G-quadruplex structures and the determination of DNA strand orientation for a given G-quadruplex structure. Signature CD spectra have previously been determined for several novel G-quadruplex structures in the presence of monovalent cations (22)(23)(24). The antiparallel-type G-quadruplexes containing alternating syn-and anti-glycosyl bond conformations have been shown to have a CD spectrum characterized by a positive CD band at ϳ295 nm, whereas parallel-type G-quadruplexes composed of all anti-glycosyl bond conformations have a positive CD band at ϳ265 nm and a negative CD band at ϳ240 nm.…”

G-quadruplex secondary structure from circular dichroism spectroscopy

“…The shapes and signs of these basis spectra for dinucleotide guanine steps are generally consistent with the results of a simplified exciton coupling approach and more refined quantum mechanical calculations used to predict the CD spectra expected for different dinucleotide stacking orientations. [3,6,17] The basis spectrum obtained for lateral and diagonal loops are highly reminiscent of CD spectra obtained for single-stranded DNA di-and trinucleotide sequences. [18] The remaining basis spectrum for "other" has low amplitude and is nearly featureless.…”

“…loop types, glycosidic bond angles, quartet stacking geometry, strand orientations, etc.) might be used to describe and classify DNA quadruplexes topologies [6, 16] , some of these may not make significant contributions to the CD signal. Since the CD of quadruplexes arises primarily from the stacking arrangements of guanine base steps within the G-quartet stacks, we have chosen the following approach to define five structural elements for each quadruplex.…”

Potential uses of G-quadruplex-forming aptamers

“…However, we should exercise caution in data interpretation because the CD spectra tends to reflect the conformation of glycosidic bonds of guanines, anti, and syn configurations in G-tetrads rather than the entire strand orientation (Figs. 2A-G) (Masiero et al 2010;Virgilio et al 2012). Nonetheless, in most cases in which unmodified sequences are used, CD spectroscopy allows for discrimination between topological conformers of G-quadruplexes on the basis of strand orientation.…”