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

Abstract

The sequence-dependent mechanical landscapes of double-stranded nucleic acids (dsNAs) 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/lengths 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 exhibits 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 (compared to atomistic simulations), very large-scale, comparative study of sequence-dependent mechanics both within and across dsNA classes, demonstrating previously hidden regulatory layers.