Systematic Approach toward Accurate and Efficient DNA Sequencing via Nanoconfinement.

Coarse-grained modeling tools are employed to simulate the mechanics of DNA loading within a nanoscale confinement and predict semiflexible polymer conformations within the confinement, providing design recommendations for DNA-sequencing devices. A workflow is developed to quantify competing requirements of efficiency and accuracy and extract metrics that guide design optimization. The mean first-passage time for DNA loading is calculated as a function of the nanochannel geometry and the applied electric field. We analyze the interplay between the free energy of confinement and the electric potential energy in achieving high-throughput, base-pair detection. The single-read probability is investigated as informative metrics for sequencing accuracy and for sensing-strategy design. High cost, low throughput, and low accuracy have so far limited the adoption of nanochannel analysis and other long-read technologies. Our work directly addresses these limitations with a systematic approach that is scalable to long molecules and complex geometries.