Concept Proposal: DNA Sequencing via Electrical Resistance During Strand Unzipping

I”m exploring a novel approach to DNA sequencing that leverages the unique electrical properties of DNA as it undergoes unzipping between two electrodes. The idea is to tether a single DNA strand between a cathode and anode, isolating the strand within a controlled microfluidic flow channel. Once anchored, the DNA is gradually unzipped—either enzymatically, thermally, or via a pH gradient—while monitoring the resistance across the strand in real time.

How It Works

DNA consists of base pairs (A-T and C-G) that have distinct bond strengths and potentially unique electrical signatures. By introducing a controlled unzipping mechanism, I hypothesize that each base pair will present a measurable change in electrical resistance as the double helix unwinds. As the unzipping progresses directionally, the system records the resistance values corresponding to each unpaired base, creating a resistance profile that could theoretically be mapped back to the DNA sequence.

Addressing Directionality

One of the key challenges is discerning between complementary base pairs (e.g., A-T vs. T-A). To tackle this, I propose anchoring the DNA with defined polarity—attaching the 5′ end to the cathode and the 3′ end to the anode. Coupled with an unzipping enzyme that progresses 5′ to 3′, this ensures that all measurements are sequence-directional. Alternatively, a temperature or pH gradient applied asymmetrically could also enforce directional unzipping.

Potential Advantages

• Direct electronic readout without the need for dyes or optics.
• Real-time data acquisition with minimal reagent requirements.
• Potential for miniaturization and integration into chip-based systems.

Next Steps

• Prototype electrode-DNA attachment methods ensuring directional binding.
• Develop controlled unzipping protocols via temperature, pH, or enzymatic methods.
• Design a high-sensitivity resistance measurement system capable of detecting base-specific variations.
• Explore data analysis techniques, potentially including machine learning, to map resistance profiles to base sequences.

This is an early-stage concept, but I believe it offers an exciting avenue for developing a new class of electronic DNA sequencing technologies. Feedback, collaborators, and insights are welcome!