Highly Conductive Nucleotide Analogue Facilitates Base-Calling in Quantum-Tunneling-Based DNA Sequencing

Area of Science:

• Biotechnology
• Nanotechnology
• Molecular Biology

Background:

• Quantum-tunneling-based DNA sequencing is a single-molecule technology with potential for high-throughput analysis.
• Current methods struggle with base-calling due to similar molecular conductance of canonical nucleotides.
• Distinguishing between the four genetic alphabets (A, T, C, G) remains a significant challenge.

Purpose of the Study:

• To enhance the molecular conductance differences between DNA nucleobases for improved quantum tunneling DNA sequencing.
• To investigate chemical modifications that can differentiate nucleotide signals.
• To provide a broadly applicable chemical strategy for single-molecule sensing and DNA sequencing.

Main Methods:

• Utilized quantum tunneling measurements to analyze DNA nucleobases.
• Replaced canonical 2'-deoxyadenosine (dA) with a highly conductive analogue, 7-deaza dA.
• Systematically evaluated molecular conductance of various dA and dG analogues.

Main Results:

• Demonstrated that replacing canonical dA with 7-deaza dA expands the molecular conductance differences between genetic alphabets.
• Revealed that nucleotide molecular conductance is highly dependent on the Highest Occupied Molecular Orbital (HOMO) level.
• Showcased that signal characteristics can be modulated by altering the HOMO level.

Conclusions:

• Chemical modification of nucleobases, specifically targeting the HOMO level, is a viable strategy to improve quantum tunneling DNA sequencing.
• The findings offer a chemical approach to facilitate single-molecule sensing and DNA sequencing.
• This research provides valuable insights for developing more efficient and accurate DNA sequencing technologies.