RNA versus DNA G-Quadruplex: The Origin of Increased Stability (original) (raw)
Related papers
The Journal of Physical Chemistry B, 2008
Molecular dynamics simulations have been used to study the differences between two DNA and RNA 14mer quadruplexes of analogous sequences. Their structures present a completely different fold: DNA forms a bimolecular quadruplex containing antiparallel strands and diagonal loops; RNA forms an intrastrand parallel quadruplex containing a G-tetrad and an hexad, which dimerizes by hexad stacking. We used a multiscale computational approach combining classical Molecular dynamics simulations and density functional theory calculations to elucidate the difference in stability of the 2-folds and their ability in coordinating cations. The presence of 2′-OH groups in the RNA promotes the formation of a large number of intramolecular hydrogen bonds that account for the difference in fold and stability of the two 14-mers. We observe that the adenines in the RNA quadruplex play a key role in conserving the geometry of the hexad. We predict the cation coordination mode of the two quadruplexes, not yet observed experimentally, and we offer a rationale for the corresponding binding energies involved.
Molecules
Quadruplexes (GQs), peculiar DNA/RNA motifs concentrated in specific genomic regions, play a vital role in biological processes including telomere stability and, hence, represent promising targets for anticancer therapy. GQs are formed by folding guanine-rich sequences into square planar G-tetrads which stack onto one another. Metal cations, most often potassium, further stabilize the architecture by coordinating the lone electron pairs of the O atoms. The presence of additional nucleic acid bases, however, has been recently observed experimentally and contributes substantially to the structural heterogeneity of quadruplexes. Therefore, it is of paramount significance to understand the factors governing the underlying complex processes in these structures. The current study employs DFT calculations to model the interactions between metal cations (K+, Na+, Sr2+) and diverse tetrads composed of a guanine layer in combination with a guanine (G)-, adenine (A)-, cytosine (C)-, thymine (T...
The study aimed to cast light on the structure and internal energetics of guanine- and xanthine-based model DNA quadruplexes and the physico-chemical nature of the non-covalent interactions involved. Several independent approaches were used for this purpose: DFT-D3 calculations, Quantum Theory of Atoms in Molecules, Natural Bond Orbital Analysis, Energy Decomposition Analysis, Compliance Constant Theory, and Non-Covalent Interaction Analysis. The results point to an excellent degree of structural and energetic compatibility between the two types of model quadruplexes. This fact stems from both the structural features (close values of van der Waals volumes, pore radii, geometrical parameters of the H-bonds) and the energetic characteristics (comparable values of the energies of formation). It was established that hydrogen bonding makes the greatest (∼50%) contribution to the internal stability of the DNA quadruplexes, whereas the aromatic base stacking and ion coordination terms are commensurable and account for the rest. Energy decomposition analysis performed for guanine (Gua) and xanthine (Xan) quartets B4 and higher-order structures consisting of two or three stacked quartets indicates that whereas Gua structures benefit from a high degree of H-bond cooperativity, Xan models are characterized by a more favorable and cooperative π-π stacking. The results of electron density topological analysis show that Na(+)/K(+) ion coordination deeply affects the network of non-covalent interactions in Gua models due to the change in the twist angle between the stacked tetrads. For Xan models, ion coordination makes tetrads in stacks more planar without changing the twist angle. Therefore, the presence of the ion seems to be essential for the formation of planar stacks in Xan-based DNA quadruplexes. Detailed study of the nature of ion-base coordination suggests that this interaction has a partially covalent character and cannot be considered as purely electrostatic. Investigation of the H-bond and ion-base coordination strengths by various independent approaches agrees well with the results of QTAIM analysis.
RNA, 2018
Uridine tetrads (U-tetrads) are a structural element encountered in RNA G-quadruplexes, for example, in the structures formed by the biologically relevant human telomeric repeat RNA. For these molecules, an unexpectedly strong stabilizing influence of a U-tetrad forming at the 3′ terminus of a quadruplex was reported. Here we present the high-resolution solution NMR structure of the r(UGGUGGU)4 quadruplex which, in our opinion, provides an explanation for this stabilization. Our structure features a distinctive, abrupt chain reversal just prior to the 3′ uridine tetrad. Similar “reversed U-tetrads” were already observed in the crystalline phase. However, our NMR structure coupled with extensive explicit solvent molecular dynamics (MD) simulations identifies some key features of this motif that up to now remained overlooked. These include the presence of an exceptionally stable 2′OH to phosphate hydrogen bond, as well as the formation of an additional K+ binding pocket in the quadrup...
Structural and energetic features of artificial DNA quadruplexes consisting of base tetrads and their stacks with Na+/K+ ion(s) inside the central pore and incorporating halogenated derivatives of xanthine: 8-fluoro-9-deazaxanthine (FdaX), 8-chloro-9-deazaxanthine (CldaX), 8-bromo-9-deazaxanthine (BrdaX), or 8-iodo-9-deazaxanthine (IdaX), have been investigated by modern state-of-the-art computational tools. The DNA (or RNA) quadruplex models based on 8-halo-9-deazaxanthines are predicted to be more stable relative to those with natural xanthine due to the increased stabilizing contributions coming from all three main types of weak interactions (H-bonding, stacking, and ion coordination). Methods for analyzing the electron density are used to understand the nature of forces determining the stability of the system and to gain a predictive potential. Quadruplex systems incorporating polarizable halogen atoms (chlorine, bromine, or iodine) benefit significantly from the stabilizing stacking between the individual tetrads due to an increased dispersion contribution as compared to xanthine and guanine, natural references used. Ion coordination induces a significant rearrangement of electron density in the quadruplex stem as visualized by electron deformation density (EDD) and analyzed by ETS-NOCV and Voronoi charges. Na+ induces larger electron polarization from the quadruplex towards the ion, whereas K+ has higher propensity to electron sharing (identified by QTAIM delocalization index). We expect that our results will contribute to the development of novel strategies to further modify and analyze the natural G-quadruplex core.
Angewandte Chemie (International ed. in English), 2016
DNA G-quadruplexes were systematically modified by single riboguanosine (rG) substitutions at anti-dG positions. Circular dichroism and NMR experiments confirmed the conservation of the native quadruplex topology for most of the DNA-RNA hybrid structures. Changes in the C8 NMR chemical shift of guanosines following rG substitution at their 3'-side within the quadruplex core strongly suggest the presence of C8-H⋅⋅⋅O hydrogen-bonding interactions with the O2' position of the C2'-endo ribonucleotide. A geometric analysis of reported high-resolution structures indicates that such interactions are a more general feature in RNA quadruplexes and may contribute to the observed preference for parallel topologies.
Unexpected Position-dependent Effects of Ribose G-quartets in G-quadruplexes
Journal of the American Chemical Society, 2017
To understand the role of ribose G-quartets and how they affect the properties of G-quadruplex structures, we studied three systems in which one, two, three, or four deoxyribose G-quartets were substituted with ribose G-quartets. These systems were a parallel DNA intramolecular G-quadruplex d(TTGGGTGGGTTGGGTGGGTT) and two tetramolecular G-quadruplexes d(TGGGT) and d(TGGGGT). Thermal denaturation experiments revealed that ribose G-quartets have position-dependent and cumulative effects on G-quadruplex stability. An unexpected destabilization was observed when rG quartets were present at the 5'-end of the G stack. This observation challenges the general belief that RNA residues stabilize G-quadruplexes. Furthermore, in contrast to past proposals, hydration is not the main factor determining the stability of our RNA/DNA chimeric G-quadruplexes. Interestingly, the presence of rG residues in a central G-quartet facilitated the formation of additional tetramolecular G-quadruplex topol...
Chemistry (Weinheim an der Bergstrasse, Germany), 2017
The topology and energetics of guanine (G) quadruplexes is governed by supramolecular interactions within their strands. In this work, we performed an extensive QM study of supramolecular interactions shaping the stems of (4+0) parallel (P) and (2+2) antiparallel (AP) systems. The large-scale (~ 400 atoms) models of P and AP were constructed from high-quality experimental structures. The results evidence that each of the P and AP structures is shaped by a distinct network of supramolecular interactions. The analysis of electron topological characteristics of H-bonds in P and AP systems indicates that the P model benefits from the stronger intra-tetrad H-bonding. For inter-tetrad stacking interactions, both NCI Plot and EDA approaches suggest that the stem of the P quadruplex benefits more from stacking as compared to the AP stem - the difference in energetic stabilization for the two topologies being ~10 %. The stronger H-bonding and stacking interactions in the stem of P quadruplex...
The role of thermodynamics and kinetics in ligand binding to G-quadruplex DNA
Chemical Communications, 2012
Molecular dynamics simulations were used to investigate the binding of four different 2,4,6-triarylpyridines to G-quadruplex DNA. Both the binding free energies, and the kinetics of binding are required to explain the measured degree of ligand induced stabilisation of the compounds, with bulky substituents having the potential to prevent the ligand from reaching the lowest energy binding site.
Strand directionality affects cation binding and movement within tetramolecular G-quadruplexes
Nucleic Acids Research, 2012
Nuclear magnetic resonance study of G-quadruplex structures formed by d(TG 3 T) and its modified analogs containing a 5 0 -5 0 or 3 0 -3 0 inversion of polarity sites, namely d(3 0 TG5 0 -5 0 G 2 T3 0 ), d(3 0 T5 0 -5 0 G 3 T3 0 ) and d(5 0 TG3 0 -3 0 G 2 T5') demonstrates formation of G-quadruplex structures with tetrameric topology and distinct cation-binding preferences. All oligonucleotides are able to form quadruplex structures with two binding sites, although the modified oligonucleotides also form, in variable amounts, quadruplex structures with only one bound cation. The inter-quartet cavities at the inversion of polarity sites bind ammonium ions less tightly than a naturally occurring 5 0 -3 0 backbone. Exchange of 15 NH + 4 ions between G-quadruplex and bulk solution is faster at the 3 0 -end in comparison to the 5 0 -end. In addition to strand directionality, cation movement is influenced by formation of an all-syn G-quartet. Formation of such quartet has been observed also for the parent d(TG 3 T) that besides the canonical quadruplex with only all-anti G-quartets, forms a tetramolecular parallel quadruplex containing one all-syn G-quartet, never observed before in unmodified quadruplex structures.