Stability of Two-quartet G-quadruplexes and Their Dimers in Atomistic Simulations

Abstract

G-quadruplexes (GQ) are four-stranded non-canonical DNA and RNA architectures that can be formed by guanine-rich sequences. The stability of GQs increases with the number of G-quartets and three G-quartets generally form stable GQs. However, stability of two-quartet GQs is an open issue. To understand the intrinsic stability of two-quartet GQ stems, we have carried out a expression. 5 Therefore, there is considerable interest in studying and modulating the formation of GQs as a means for controlling gene expression and other cellular processes. 6 GQs are formed by stacking of planar guanine quartets, creating the G-stem. The O6 atoms of all the guanines face to form a central electron-rich channel within the GQ where cations bind and coordinate with the O6 atoms. This coordination is essential for GQ stability. 7 Bases not involved in G-stem belong to bulges, flanking nucleotides or participate in the loops linking the G-strands of the GQs. 3The GQs can be monomolecular, bimolecular or tetramolecular depending on the number of DNA or RNA molecules that form the GQ. 8,9 The topologies of GQs are highly variable as the G-strand orientation can be parallel or antiparallel and based on that GQs can fold into parallel, antiparallel or hybrid topology. 10,11 The guanines in the DNA GQs can adopt syn or anti orientation. 10,12,13 In the RNA GQs, the 2 -hydroxyl group in ribose allows for more interactions with the bases, cations and water molecules thereby increasing their stability, as common in RNA molecules. [14][15][16][17][18][19] It also restricts the orientation of the guanine bases favouring the anti-orientation. 14 Therefore, the majority of the RNA GQs have been observed in the parallel-stranded topology with all bases in the anti-orientation. [15][16][17][18] The loops further add to the diversity as the GQs can have propeller, lateral or diagonal loops. 8,[20][21][22][23][24][25][26][27] The parallel-stranded GQ have propeller (double-chain reversal) loops as they are necessary to orient the following and preceding G-strands in a parallel arrangement. 8 The antiparallel and hybrid GQs can have various combinations of the three loop types. [20][21][22][23][24][25][26][27] The overall GQ topology dictates the loop combination as well as the allowable syn-anti patterns of the guanines. Na + ions tend to coordinate within the plane while K + ions coordinate between the planes of the G-quartets. 28,29 The cation-quadruplex interactions can induce kinetic and equilibrium differences between the different topologies. 28,30,31 Stability of GQs is affected by the number of G-quartets in the stem. 14,[32][33][34] It is commonly accepted that increasing the number of G-quartets usually stabilizes the GQ structure. 12,14,34,35 In DNA, stable GQ structures generally involve three quartets or more, although stable antiparallel two-quartet GQs with loop alignments or stacked triads have also been observed. 21, 36 27 In such GQs, additional interactions formed by the loops or triads above and/or below the G-stems contribut...

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