A major goal in medical research is to develop a DNA sequencing technique that is capable of reading an entire human genome at low cost. Recently, it was proposed that DNA sequencing could be performed by measuring the electron transport properties of the individual nucleotides in a DNA molecule. Here, we report electrical detection of single nucleotides using two configurable nanoelectrodes and show that electron transport through single nucleotides occurs by tunnelling. We also demonstrate statistical identification of the nucleotides based on their electrical conductivity, thereby providing an experimental basis for a DNA sequencing technology based on measurements of electron transport.

One major challenge of nanopore-based DNA sequencing technology is to find an efficient way to reduce DNA translocation speed so that each nucleotide can reside long enough in the pore for interrogation. Here we report the electrical tuning of DNA translocation speed by gate modulation of nanopore wall surface charges. We find that native surface-charge-induced counterions in the electroosmotic layer substantially enhance advection flow of fluid, which exerts stronger dragging forces on the translocating DNA, and thereby lowering the DNA translocation speed. We propose a feedback device architecture to regulate DNA translocation by modulating the effective wall surface charge density σw*via lateral gate voltages--at the beginning, a positive gate bias is applied to weaken σw* in order to enhance the capture rate of DNA molecule; upon detection of ionic current variance indicating DNA has been driven into the nanopore, gate bias is turned to be negative so that σw* is reinforced and DNA translocation is retarded. We show that a gate electric field can dramatically decrease the DNA translocation speed at a rate about 55 μm/s per 1 mV/nm.

The self-breaking mechanism of gold junctions is studied by investigating stability of the atom-sized contacts. The single atom contact lifetime increases from about 0.02 to 200 s upon decreasing the junction stretching speed, while at the same time, the breaking force diminishes logarithmically. We find that the junction self-breaking processes involve sufficient atomic rearrangements, which thereby allow complete self-compensation of externally introduced strain at 0.8 pm/s. The present results have important implications on fabrication of stable single molecule junctions.

Two paradigm shifts in DNA sequencing technologies—from bulk to single molecules and from optical to electrical detection—are expected to realize label-free, low-cost DNA sequencing that does not require PCR amplification. It will lead to development of high-throughput third-generation sequencing technologies for personalized medicine. Although nanopore devices have been proposed as third-generation DNA-sequencing devices, a significant milestone in these technologies has been attained by demonstrating a novel technique for resequencing DNA using electrical signals. Here we report single-molecule electrical resequencing of DNA and RNA using a hybrid method of identifying single-base molecules via tunneling currents and random sequencing. Our method reads sequences of nine types of DNA oligomers. The complete sequence of 5′-UGAGGUA-3′ from the let-7 microRNA family was also identified by creating a composite of overlapping fragment sequences, which was randomly determined using tunneling current conducted by single-base molecules as they passed between a pair of nanoelectrodes.

Understanding biophysics governing DNA capture into a nanopore and establishing a manipulation system for the capture process are essential for nanopore-based genome sequencing. In this work, the functionality of extended electric field and electroosmotic flow (EOF) during the capture stage and their dependence on gate voltage, U(G), are investigated. We demonstrate that while both the electric field and EOF within a cis chamber make long-distance contributions to DNA capture around the pore mouth, the former effect is always capturing, while the latter causes trapping or blocking of the molecule depending on the magnitude of the gate voltage, U(G): an anionic EOF induced by high U(G) is capable of doubling the DNA trapping speed and thus the absorption radius in the cis chamber, whereas a cationic EOF by low U(G) would substantially offset the trapping effort by the electric field and even totally block DNA entrance into the pore. Based on the analysis, a gate regulation is proposed with the objective of achieving a high DNA capture rate while maintaining a low error rate.

Post-translational modifications alter the properties of proteins through the cleavage of peptide bonds or the addition of a modifying group to one or more amino acids. These modifications allow proteins to perform their primary biological functions, but single-protein studies of post-translational modifications have been hindered by a lack of suitable analysis methods. Here, we show that single amino acids can be identified using electron tunnelling currents measured as the individual molecules pass through a nanoscale gap between electrodes. We identify 12 different amino acids and the post-translational modification phosphotyrosine, which is involved in the process that switches enzymes on and off. Furthermore, we show that the conductance measurements can be used to partially sequence peptides of an epidermal growth factor receptor substrate, and can discriminate a peptide from its phosphorylated variant.

We explored single-particle translocation through a low thickness-to-diameter aspect ratio Si(3)N(4) pore mimicking graphene nanopore structure by a resistive pulse method. Ionic conductance of 0.05 aspect ratio pores scales linearly with the diameter, indicating predominant contribution of the access resistance to the ion transport. We find that the access resistance changes little during particle translocation. Furthermore, we observe enhanced particle capture rates via the strong electric field extended outside the low-aspect-ratio pore mouth. We also demonstrate electrical discrimination of two different sized particles using the low-aspect-ratio pore sensor with the constant access resistance assumption. The present findings indicate the potential utility of nucleotide-sized graphene nanopores as an electrical sensing platform for single-base identification via transmembrane ionic current blockade detections.

The symmetry of a molecule junction has been shown to play a significant role in determining the conductance of the molecule, but the details of how conductance changes with symmetry have heretofore been unknown. Herein, we investigate a naphthalenedithiol single-molecule system in which sulfur atoms from the molecule are anchored to two facing gold electrodes. In the studied system, the highest single-molecule conductance, for a molecule junction of 1,4-symmetry, is 110 times larger than the lowest single-molecule conductance, for a molecule junction of 2,7-symmetry. We demonstrate clearly that the measured dependence of molecule junction symmetry for single-molecule junctions agrees with theoretical predictions.