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…
The study explores the sequence-dependent mechanical landscapes of double-stranded nucleic acids (dsNA), with a focus on double-stranded RNA (dsRNA), DNA-RNA hybrids, and epigenetically modified double-stranded DNA (dsDNA). A coarse-grained predictive model called cgNA+ was developed to simulate the mechanics of these dsNA types, using data from a mere 1.26 milliseconds of atomistic simulations.
The model accurately predicts the non-local sequence-dependent equilibrium shape and stiffness of these dsNA structures, with errors an order of magnitude smaller than those observed in previous sequence-variability studies.
The research highlights the strong influence of flanking sequence up to an octamer context on the equilibrium shape of dsNA. Flexible dimer-steps were found to be more context-sensitive. Modification of CpG sites was shown to alter the equilibrium shape of dsNA as significantly as single-nucleotide polymorphisms. The groove width analysis across dsNA decamers revealed strong sequence dependence, reflecting the differing characteristic helical geometries of dsDNA and dsRNA. However, DRHs exhibited mixed behavior depending on the pyrimidine content of the DNA strand.
Cancer-related transcription factor CTCF binding sites demonstrated a distinct groove width signature. The persistence-length spectra from over [~]9 million sequences indicated that dsRNA is stiffer than dsDNA. However, DRH showed intermediate stiffness that was modulated by the DNA strand's pyrimidine content. Interestingly, persistence length increased upon CpG modification, but decreased upon hypermodification.
In conclusion, the cgNA+ model allows for the first highly accurate, very large-scale, and comparative study of sequence-dependent mechanics across different dsNA classes. This study uncovers previously hidden regulatory layers in the mechanics of dsNA, providing new insights into their sequence-dependent behavior.
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