Effects of deficient of the Hoogsteen base-pairs on the G-quadruplex stabilization and binding mode of a cationic porphyrin

Abstract

BackgroundIn stabilization of the G-quadruplex, formation of a Hoogsteen base-pair between the guanine (G) bases is essential. However, the contribution of each Hoogsteen base-pair at different positions to whole stability of the G-quadruplex has not been known. In this study, the effect of a deficiency of the Hoogsteen type hydrogen bond in the G-quadruplex stability was investigated. Spectral properties of meso-tetrakis(1-methylpyridinium-4-yl)porphyrin (TMPyP) associated with various G-quadruplexes were also examined.MethodsThe thermal stability of the thrombin-binding DNA aptamer 5′G1G2TTG5G6TG8TG10G11TTG14G15 G-quadruplex, in which the guanine (G) base at 1, 2, 5, 6 and 8th positions was replaced with an inosine (I) base, one at a time, was investigated by circular dichroism (CD). The absorption, CD and fluorescence decay curve for the G-quadruplex associated TMPyP were also measured.ResultsThe transition from the G-quadruplex to a single stranded form was endothermic and induced by an increase in entropy. The order in stability was 0>8>6>2>5>1, where the numbers denote the position of the replacement and 0 represents no replacements of the G base, suggesting the significant contribution of the G1 base in the stability of the G-quadruplex. Alteration in the spectral property of TMPyP briefly followed the order in thermal stability.ConclusionsReplacement of a G base with an I base resulted in destabilization of the G-quadruplex. The missing hydrogen bond at position 1 destabilized the G-quadruplex most efficiently. TMPyP binds near the I base-replaced location namely, the side of the G-quadruplex.General significanceThe Hoogsteen base-pairing is confirmed to be essential in stabilization of G-quadruplex. When G is replaced with I, the latter base is mobile to interact with cationic porphyrin.

The diverse structural landscape of quadruplexes

“…The formation of G‐quadruplexes is predominantly driven by metal ion binding, hydrogen bonding, π‐π stacking interactions between tetrads and water release . Van der Waals effects and ionic effects (ion condensation and Debye‐Hückel counter‐ion atmosphere) are also thought to contribute to G‐quadruplex formation .…”

Forever Young: Structural Stability of Telomeric Guanine Quadruplexes in the Presence of Oxidative DNA Lesions**

“…From a structural point of view, G4s are constituted by a quartet of guanine bases forming planar arrangements (tetrads) and are stabilized by Hoogsteen type hydrogen bonds. [8] These latter non-covalent interactions, have been most notably shown to present a high degree of cooperativity, also justifying the extremely high rigidity of the G4 core. [9][10][11] The formation of the tetrad arrangement is accompanied by the accumulation of a quite important negative charge, that could lead to electrostatic repulsion in the center of the quartet, compromising the global stability.…”

Forever Young: Structural Stability of Telomeric Guanine-Quadruplexes in Presence of Oxidative DNA Lesions

“…From a structural point of view, G4s are constituted by a quartet of guanine bases forming planar arrangements (tetrads) and are stabilized by Hoogsteen type hydrogen bonds. 8 These latter noncovalent interactions, have been most notably shown to present a high degree of cooperativity, also justifying the extremely high rigidity of the G4 core. [9][10][11] The formation of the tetrad arrangement is accompanied by the accumulation of a quite important negative charge, that could lead to electrostatic repulsion in the center of the quartet, compromising the global stability.…”

“…From a structural point of view, G4s are constituted by a quartet of guanine bases forming planar arrangements (tetrads) and are stabilized by Hoogsteen type hydrogen bonds. 8 These latter non-covalent interactions, have been most notably shown to present a high degree of cooperativity, also justifying the extremely high rigidity of the G4 core. 9–11…”