Sequence-dependent conformational and mechanical landscapes of double-stranded nucleic acids

The sequence-dependent mechanical landscapes of double-stranded nucleic acid (dsNA) remain largely unexplored beyond canonical dsDNA. We describe cgNA+, a coarse-grained predictive model of the mechanics of dsRNA, DNA:RNA hybrids, and epigenetically modified dsDNA, all parameterised from 1.26 milliseconds of atomistic simulations. cgNA+ predicts non-local sequence-dependent equilibrium shape and stiffness with errors an order of magnitude smaller than sequence-variability, while enabling exploration of numbers of sequences inaccessible to atomistic simulation. We show that dsNA equilibrium shape is strongly influenced by flanking sequence up to octamer context, with flexible dimer-steps more context-sensitive. CpG-modification alters equilibrium shape comparable to changes caused by single-nucleotide polymorphisms. Groove width analysis across dsNA decamers reveals strong sequence dependence, reflecting the differing characteristic helical geometry of dsDNA and dsRNA, whereas DRHs exhibit mixed behaviour depending on DNA-strand pyrimidine content. CTCF binding sites exhibit a distinct groove width signature. Persistence-length spectra from [~] 9 million sequences indicate that dsRNA is stiffer than dsDNA, whereas DRH exhibit intermediate stiffness modulated by DNA strand pyrimidine content. Persistence length increases upon CpG-modification, but decreases on hypermodification. Overall, the cgNA+ model enables a first, highly accurate, very large-scale, comparative study of sequence-dependent mechanics both within and across dsNA classes, demonstrating previously hidden regulatory layers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/740023v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@6de6acorg.highwire.dtl.DTLVardef@1435181org.highwire.dtl.DTLVardef@9c2b60org.highwire.dtl.DTLVardef@e3abf0_HPS_FORMAT_FIGEXP M_FIG C_FIG