Expanding the Topological Landscape by a G‐Column Flip of a Parallel G‐Quadruplex

Abstract

Canonical G-quadruplexes can adopt a variety of different topologies depending on the arrangement of propeller, lateral, or diagonal loops connecting the four Gcolumns. A novel intramolecular G-quadruplex structure is derived through inversion of the last G-tract of a threelayered parallel fold, associated with the transition of a single propeller into a lateral loop. The resulting (3 + 1) hybrid fold features three syn•anti•anti•anti G-tetrads with a 3'-terminal all-syn G-column. Although the ability of forming a duplex stem-loop between G-tracts seems beneficial for a propellerto-lateral loop rearrangement, unmodified G-rich sequences resist folding into the new (3 + 1) topology. However, refolding can be driven by the incorporation of syn-favoring guanosine analogues into positions of the fourth G-stretch. The presented hybrid-type G-quadruplex structure as determined by NMR spectroscopy may provide for an additional scaffold in quadruplex-based technologies.

Indoloquinoline Ligands Favor Intercalation at Quadruplex‐Duplex Interfaces

“…[3][4][5][6] Upon the engineering of quadruplex scaffolds, duplex extensions in quadruplexes were shown to promote quadruplex folding or to drive folding into defined quadruplex topologies. [7][8][9][10] Also, RNA Q-D junctions were reported to be specifically recognized by the human fragile X mental retardation RGG peptide [11,12] and anti-thrombotic quadruplexes featuring Q-D interfaces have demonstrated their great potency as biomedical aptamers. [13,14] Consequently, Q-D junctions have started to become attractive candidates as therapeutic targets but also as novel structural motifs with promising properties.…”

“…In fact, several natural and designed quadruplex‐forming sequences fold to feature Q‐D interfaces by having loops, bulges, or flanking sequences able to self‐associate into a duplex hairpin [3–6] . Upon the engineering of quadruplex scaffolds, duplex extensions in quadruplexes were shown to promote quadruplex folding or to drive folding into defined quadruplex topologies [7–10] . Also, RNA Q‐D junctions were reported to be specifically recognized by the human fragile X mental retardation RGG peptide [11,12] and anti‐thrombotic quadruplexes featuring Q‐D interfaces have demonstrated their great potency as biomedical aptamers [13,14] .…”

High-affinity binding at quadruplex–duplex junctions: rather the rule than the exception

“…In contrast, non-canonical G4 structures with unique structural motifs ( 8 ) but especially quadruplex–duplex (Q–D) junctions may provide for a more selective high-affinity targeting through low molecular weight compounds. Additionally, they may also be used as powerful tools to enforce a particular G4 topology or to optimize aptamer affinities ( 9–13 ). Q–D junctions are expected to frequently occur within the genome ( 14–16 ).…”

The Ubiquity of High-Energy Nanosecond Fluorescence in DNA Duplexes

“…It could be further tested by varying the types of loops and/or the peripheral bases located within the loops. Thus, structures with lateral loops would be interesting, because they preclude CT interactions between guanines of the quadruplex core and the peripheral bases. Alternatively, modification of the type of the peripheral bases [i.e., G-quadruplexes formed by folding of (G 3 C) 3 G 3 or (G 3 T) 3 G 3 strands] or their number [i.e., (G 3 T) 3 G 3 vs (G 3 T 2 ) 3 G 3 )] while maintaining the parallel arrangement of guanines in the core, should shed some light on the factors affecting HENE.…”