Geometric Formalism for DNA Quadruplex Folding

Abstract

Understanding the control of self-assembly and stereochemical properties of DNA higher order architectural folds is of fundamental importance in biology as well as biochemical technological applications. Guanine-rich DNA sequences can form tetrahelical architectures termed quadruplexes. A formalism is presented describing the interdependency of a set of structural descriptors as a geometric basis for folding of unimolecular quadruplex topologies. It represents a standard for interpretation of structural characteristics of quadruplexes, and is comprehensive in explicitly harmonizing the results of published literature with a unified language. The formalism is a fundamental step towards prediction of unimolecular quadruplex folding topologies from primary sequence.

Folding Topology of a Bimolecular DNA Quadruplex Containing a Stable Mini-hairpin Motif within the Diagonal Loop

“…1), propeller loops or even with a mixture of different loops, and G-tetrads with combinations of syn and anti glycosidic bond angles. 40,41 In turn, specific loop arrangements can give rise to different strand orientations and polarities. For each particular model, the individual tetrads can form in a clockwise or anticlockwise manner, increasing the number of permutations for each model, each with intrinsically different degrees of symmetry that will be manifested in the NMR spectrum in terms of the number of resonances.…”

“…3,30 In short, the evidence for loop-dependent folding of G-quadruplexes is significant and suggests a high level of sensitivity to point mutations and loop-specific interactions that lead to a complex relationship between fold and sequence. This is underpinned by an intrinsically high degree of structural plasticity, 40,51 and ample scope for the design of quadruplex-specific ligands with anti-cancer activity. 52 …”

Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives

“…But loops (diagonal, lateral, and propeller) and width of the grooves (narrow, medium and wide) are differed for each quadruplex considerably. 34 Furthermore, there are considerable differences in the structures reported for native quadruplexes (without ligand) and quadruplex-ligand complexes as ligand-induced binding pockets are created in the later due to rearrangement of the flexible loops or flanking nucleotides. 35,36 Therefore, these flexible loops and unique groove widths 34 need to be considered along with the large π surface area of quartet for achieving specific binding of small molecule to the targeted quadruplex topology.…”

Anomeric DNA quadruplexes

“…NMR data support the formation of two G quartets and one TT base pair, thus implying the presence of two lateral loops. 34 Additionally, it should be taken into account that unlike natural β anomers, α nucleosides cannot adopt a syn conformation. 33 Therefore, two α-deoxyguanosine strands must be arranged in parallel.…”