Guanine base stacking in G-quadruplex nucleic acids

Abstract

G-quadruplexes constitute a class of nucleic acid structures defined by stacked guanine tetrads (or G-tetrads) with guanine bases from neighboring tetrads stacking with one another within the G-tetrad core. Individual G-quadruplexes can also stack with one another at their G-tetrad interface leading to higher-order structures as observed in telomeric repeat-containing DNA and RNA. In this study, we investigate how guanine base stacking influences the stability of G-quadruplexes and their stacked higher-order structures. A structural survey of the Protein Data Bank is conducted to characterize experimentally observed guanine base stacking geometries within the core of G-quadruplexes and at the interface between stacked G-quadruplex structures. We couple this survey with a systematic computational examination of stacked G-tetrad energy landscapes using quantum mechanical computations. Energy calculations of stacked G-tetrads reveal large energy differences of up to 12 kcal/mol between experimentally observed geometries at the interface of stacked G-quadruplexes. Energy landscapes are also computed using an AMBER molecular mechanics description of stacking energy and are shown to agree quite well with quantum mechanical calculated landscapes. Molecular dynamics simulations provide a structural explanation for the experimentally observed preference of parallel G-quadruplexes to stack in a 5′–5′ manner based on different accessible tetrad stacking modes at the stacking interfaces of 5′–5′ and 3′–3′ stacked G-quadruplexes.

Insights into G-quadruplex specific recognition by the DEAH-box helicase RHAU: Solution structure of a peptide–quadruplex complex

“…5). The binding at the 3′ end occurs at a higher peptide concentration than the binding at the 5′ end, indicating a lower affinity for the 3′-end bottom site (SI Appendix, arrangements of the backbone and orientations of the sugars between the 5′-and 3′-end G-tetrads (32). In principle, the fulllength RHAU should be able to recognize both the 5′ and 3′ end; however, it remains to be established whether the protein can bind the two ends simultaneously and how this binding assists in resolving G4 structures.…”

Structural Variations and Solvent Structure of r(UGGGGU) Quadruplexes Stabilized by Sr2+ Ions

“…As outlined in Fig. 1, three distinct bonding effects contribute to this stability: eight hydrogen bonds that link the Hoogsteen face of each guanine to the Watson–Crick face of its neighbor occur in each quartet; a universally present, dehydrated, central cation forms electrostatic links to the O6 carbonyl oxygen atoms of four or eight surrounding guanines; and the planes of adjacent quartets are offset at angles that favor π–π stacking interactions [3,14]. …”

“…Capping the regularly spaced column of stacked G4 quartets poses an interesting structural challenge for quadruplex nucleic acid conformation [14]. A thymine tetrad at the 5′ terminus of a parallel-stranded TGGGGT quadruplex was reported by Cáceres et al .…”

Multiscale simulation of DNA

“…Similar conclusions on the strengthand limitations of QM theory applied to nucleic acids were obtainedby the same group in their study of the Sarcin-Ricin internal loop [10].Following similar ideas and approaches other groups have recently explored specific details of nucleobase interactions in c tain ty s f DNA. F xam l , Phan's g u cha act iz d th guanin bas stacking in Gquadruplex nucleic acids [11], and Parker and coworkers described the nature of - stacking of nucleobases using symmetry adapted perturbation theory (SAPT), finding good predictive power, but detecting again the limitations implicit to the reduced size of the model systems [12••]. Nawort and coworkers used DFT theory to analyze the impact of the presence of 2'thi u idin and d g adati n ducts in tRNA n the fidelity of the translation process [13], and Brovarets & H v un us d Bad 's th y and DFT MP2 calculati ns t cha act iz the probability of occurrence of ground-state tautomerization of the G-C Watson-Crick base pairby a double proton transfer (DPT) [14].…”