Quantum Point Contact Single-Nucleotide Conductance with Conformational Smear Characterization for DNA and RNA Sequence Identification

Nanoelectronic nucleic acid sequencing has been hindered by unreliable metal-molecule junction formation and variable molecular conformations [1]. We describe a quantum point contact single-nucleotide conductance sequencing (QPICS) method that enables reproducible conductance measurements of conformationally constrained single nucleotides within electrostatically bound DNA and RNA molecules on a self-assembled cysteamine monolayer [2]. We quantify conformational variation, or smear, from the distance over which molecular junctions are maintained during each conductance measurement, and apply an advanced algorithmic approach for accurate nucleotide identification from single measurements [2,3]. Varying the applied bias and pH conditions allows molecular conductance to be switched ON/OFF to achieve >99.7% accuracy for base calling with minimal repeat measurements (~12), surpassing the accuracy of existing sequencing methods. The results demonstrate the potential for using simple surface modifications and existing biochemical moieties in nucleobases for reliable single-molecule, nanoelectronic DNA and RNA nucleotide identification.
[1] Korshoj, et al. Small 2017, 13, 1603033
[2] Afsari, et al. ACS Nano 2017, acsnano.7b05500
[3] Korshoj, et al. J. Am. Chem. Soc. 2017, jacs.7b08246