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bioRxiv · 10.64898/2026.08.09.740023

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

Sharma, R.·Patelli, A. S.·Singh, R.·Petkeviciute-Gerlach, D.·Gonzalez, O.·Maddocks, J. H.
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Abstract

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@1a430edorg.highwire.dtl.DTLVardef@88469borg.highwire.dtl.DTLVardef@d3a7eforg.highwire.dtl.DTLVardef@1b65a15_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sharma, R., Patelli, A. S., Singh, R., Petkeviciute-Gerlach, D., Gonzalez, O., Maddocks, J. H.. 2026-08-10. Sequence-dependent conformational and mechanical landscapes of double-stranded nucleic acids. https://doi.org/10.64898/2026.08.09.740023

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