Sequence-dependent conformational and mechanical landscapes of double-stranded nucleic acids
- 1Institute of Mathematics, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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.
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BibTeX
@misc{sharma2026sequencedependent,
title = {{Sequence-dependent conformational and mechanical landscapes of double-stranded nucleic acids}},
author = {R. Sharma and A. S. Patelli and R. Singh and D. Petkeviciute-Gerlach and O. Gonzalez and J. H. Maddocks},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.09.740023},
url = {https://www.biorxiv.org/content/10.64898/2026.08.09.740023v2},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Sequence-dependent conformational and mechanical landscapes of double-stranded nucleic acids
AU - R. Sharma
AU - A. S. Patelli
AU - R. Singh
AU - D. Petkeviciute-Gerlach
AU - O. Gonzalez
AU - J. H. Maddocks
PY - 2026
DA - 2026/08/09
PB - bioRxiv
DO - 10.64898/2026.08.09.740023
UR - https://www.biorxiv.org/content/10.64898/2026.08.09.740023v2
AB - 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.
ER -