Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the G*GC and T*AT Triplets

Abstract

Implications of DNA, RNA and RNA.DNA hybrid triplexes in diverse biological functions, diseases and therapeutic applications call for a thorough understanding of their structure-function relationships. Despite exhaustive studies mechanistic rationale for the discriminatory preference of parallel DNA triplexes with G*GC & T*AT triplets still remains elusive. Here, we show that the highest nonisostericity between the G*GC & T*AT triplets imposes extensive stereochemical rearrangements contributing to context dependent triplex destabilisation through selective disruption of Hoogsteen scheme of hydrogen bonds. MD simulations of nineteen DNA triplexes with an assortment of sequence milieu reveal for the first time fresh insights into the nature and extent of destabilization from a single (non-overlapping), double (overlapping) and multiple pairs of nonisosteric base triplets (NIBTs). It is found that a solitary pair of NIBTs, feasible either at a G*GC/T*AT or T*AT/G*GC triplex junction, does not impinge significantly on triplex stability. But two overlapping pairs of NIBTs resulting from either a T*AT or a G*GC interruption disrupt Hoogsteen pair to a noncanonical mismatch destabilizing the triplex by ~10 to 14 kcal/mol, implying that their frequent incidence in multiples, especially, in short sequences could even hinder triplex formation. The results provide (i) an unambiguous and generalised mechanistic rationale for the discriminatory trait of parallel triplexes, including those studied experimentally (ii) clarity for the prevalence of antiparallel triplexes and (iii) comprehensive perspectives on the sequence dependent influence of nonisosteric base triplets useful in the rational design of TFO’s against potential triplex target sites.

Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

“…S4 , S5 ). This is not surprising because the residual twist and radial difference, the measures of base pair nonisostericity 59 – 62 , between the G…G and G…C base pairs (Supplementary Fig. S12 ) are insignificant compared with that of A…A and G…C base pairs.…”

m1A and m1G disrupt A-RNA structure through the intrinsic instability of Hoogsteen base pairs

“…H-bond presence was evaluated using CHARMM’s COOR HBOND module for each trajectory with cutoff distance and angle of 3.6 Å, and 120° following Goldsmith et al 90 .…”

Energy Landscapes and Hybridization Pathways for DNA Hexamer Duplexes

“…Hence, again, entropic effects appear to play an important role in stabilizing the canonical WC duplex, as opposed to defective or higher-order structures, at physiological temperatures. 60,61 Figure 3: Top: The fastest free energy zippering pathway between the conformational ensembles corresponding to dissociated (A) and fully-hybridized (B) states for d(GGGGGG). The points correspond to groups of minima and transition states, obtained by the recursive regrouping scheme 53,54 using a barrier threshold of 5.5 kcal mol −1 .…”