Searching for Sequence Features that Control DNA Cyclizability

The mechanical properties of DNA molecules are crucial in many biological processes, from DNA packaging to transcription regulation. While the mechanics of long DNA typically follow the worm-like chain polymer model, multiple studies have shown that the mechanics of short DNA - at the length scale of DNA-protein interactions - depend strongly on its sequence content. Motivated by recent high-throughput measurements of sequence-dependent DNA cyclizability - the DNAs tendency to mechanically bend and form a loop, we developed a statistical mechanics approach to systematically explore how cyclizability depends on interactions between individual nucleotides in the sequence. By applying this method to datasets of randomly generated and biologically derived sequences, we identified characteristic sequence features that control DNA cyclizability and extracted the most and least cyclizable sequences, the behavior of which we validated through all-atom molecular dynamics simulations. We found that while highly cyclizable sequences share the same periodic features across datasets, distinct sequence patterns can result in low cyclizability. This work contributes to our understanding of the sequence dependence of DNA mechanics and its role in various biological processes, and has implications for the growing field of DNA nanofabrication.