Digital unzipping of DNA through a solid-state nanopore: A theoretical study for base-by-base ratcheting

TL;DR

This paper proposes a theoretical model for a protein-free, solid-state nanopore DNA sequencing method that uses a reversible electrostatic hold and unzipping mechanism to achieve accurate, base-by-base DNA translocation.

Contribution

It introduces a novel theoretical framework combining DNA unzipping and electrostatic hold mechanisms for nanopore sequencing without proteins.

Findings

Submicrosecond switching enables <5% error rate.

Reversible electrostatic hold improves DNA translocation control.

Theoretical demonstration of deterministic single-base motion.

Abstract

Solid-state nanopore DNA sequencers present mechanical and chemical stability, reusability, and large-scale integrability. However, their development is hindered by the absence of a protein-free mechanism for controlling DNA translocation, which is accomplished by motor proteins in their biological counterparts. Here, we propose and theoretically analyze a protein-independent ratchet mechanism based on the unzipping of double-stranded DNA at the nanopore rim. When the transmembrane bias exceeds a certain threshold, the base pairs mechanically dissociate, allowing one strand to translocate while the other remains upstream. This unzipping process is known to slow DNA motion, suggesting that voltage pulses can trigger individual unzipping events at externally defined times, a concept referred to as digital unzipping. However, the intrinsic unzipping barrier is insufficient to provide the dwell times required for a reliable ionic-current readout; therefore, an additional mechanism is needed to hold the DNA in place between voltage pulses. To overcome this limitation, we introduce a reversible hold mechanism implemented via electrostatic attraction between DNA and a charged nanopore wall, which temporarily immobilizes the strand once the unzipping fork catches on the nanopore rim. Using a statistical-mechanical model, we track the evolution of the mean and variance of DNA position through each ratchet cycle. Analytical expressions for the corresponding error probabilities show that submicrosecond switching of the hold mechanism enables base-by-base stepping with an error rate <5%. These results theoretically demonstrate that digital unzipping combined with a reversible hold mechanism can yield deterministic single-base motion, thus opening a viable route toward all-solid-state nanopore sequencing.