Tunneling junctions for sequencing

Abstract

Molecules may be analyzed (e.g., sequencing of nucleic acid molecules) by tunneling recognition at a tunneling junction. Embodiments of the present invention may allow detecting individual nucleotides and the sequencing of a nucleic acid molecule using a tunneling junction. By labeling a specific nucleotide with a moiety, tunneling junctions may generate a signal with a suitable signal-to-noise ratio. The tunneling recognition uses a tunneling current that is mostly through the moiety rather than mostly through the nucleotide or a portion of the molecule of interest. Because a single nucleotide can be detected with a signal with a suitable signal-to-noise ratio resulting from the tunneling current passing through the moiety, embodiments of the present invention may allow for fast detection of nucleotides using a tunneling current.

What is claimed is: 
     
         1 . A system for analyzing nucleic acid molecules, the system comprising:
 a tunneling junction comprising a first conductor and a second conductor separated by an insulating layer;   a polymerase attached to the tunneling junction and connected to a template parent strand, the polymerase configured to elongate a nascent strand that is hybridized to the template parent strand;   a power supply in electrical communication with at least one of the first conductor and the second conductor;   a set of nucleotides, each nucleotide of the set of nucleotides attached to a label compound comprising a moiety,   a meter device configured to measure a value of a characteristic through the first conductor and the second conductor via the moiety, the characteristic being an electrical characteristic or a magnetic characteristic; and   a non-transitory computer readable medium storing a plurality of instructions, the plurality of instructions, when executed by a processor, cause the processor to:
 measure the value of the characteristic through the first conductor and the second conductor, 
 compare the value of the characteristic to a reference value of the characteristic, and 
 upon determining the value exceeds the reference value, detect a nucleotide as being hybridized to the template parent strand. 
   
     
     
         2 . The system of  claim 1 , further comprising:
 a reservoir in fluid communication with the tunneling junction,   an injection system configured to deliver a liquid from the reservoir to the tunneling junction.   
     
     
         3 . The system of  claim 1 , wherein:
 the system comprises a plurality of tunneling junctions, and   the power supply is in electrical communication with the plurality of tunneling junctions.   
     
     
         4 . The system of  claim 1 , wherein:
 the first conductor is a first electrode,   the second conductor is a second electrode,   the tunneling junction is disposed on a surface of a substrate,   the insulating layer has a surface parallel to the surface of the substrate, and the characteristic is the electrical characteristic.   
     
     
         5 . The system of  claim 4 , wherein the polymerase is attached to the tunneling junction at the insulating layer at the surface parallel to the substrate. 
     
     
         6 . The system of  claim 4 , wherein the insulating layer comprises alumina (Al 2 O 3 ), hafnia (HfO 2 ), silicon nitride (Si 3 N 4 ), silicon oxide (SiO 2 ), glass, quartz, magnesium oxide (MgO), titanium dioxide (TiO 2 ), or zirconium dioxide (ZrO 2 ). 
     
     
         7 . The system of  claim 4 , wherein the first electrode comprises gold, silver, platinum, or palladium. 
     
     
         8 . The system of  claim 4 , wherein the electrical characteristic is current. 
     
     
         9 . The system of  claim 4 , wherein the insulating layer is characterized by a thickness greater than 2 nm. 
     
     
         10 . The system of  claim 1 , wherein:
 the first conductor comprises a first ferromagnetic material, and   the second conductor comprises a second ferromagnetic material.   
     
     
         11 . The system of  claim 10 , wherein:
 the first ferromagnetic material and the second ferromagnetic material independently comprise:
 cobalt; Co/I/La ⅔ Sr ⅓ MnO 3  (LSMO) where I is SrTiO 3  (STO), Ce 0.69 La 0.31 , or O 1.845  (CLO); CoGd; CoPt; CoFe; CoFeB; CoFeTb; iron; Fe 2 O 3;  FeOFe 2 O 3 ; NiOFe 2 O 3 ; CuOFe 2 O 3 ; MgOFe 2 O 3 ; MnBi; Ni; MnSb; MnOFe 2 O 3 ; Y 3 Fe 5 O 12 ; MnAs; Gd; Tb; Dy; or EuO. 
   
     
     
         12 . The system of  claim 10 , wherein the moiety is selected from the group consisting of a ferromagnetic material or superparamagnetic material. 
     
     
         13 . The system of  claim 10 , wherein the polymerase is attached to the tunneling junction at the insulating layer. 
     
     
         14 . The system of  claim 10 , wherein the characteristic is the electrical characteristic, and the electrical characteristic is current. 
     
     
         15 . The system of  claim 1 , wherein the thickness of the insulating layer is greater than the size of each moiety of each nucleotide of the set of nucleotides. 
     
     
         16 . The system of  claim 1 , wherein:
 each nucleotide of the set of nucleotides is attached to a cleavable linker, and   the cleavable linker is attached to the moiety.   
     
     
         17 . The system of  claim 16 , wherein the nucleotide is directly bonded to the cleavable linker. 
     
     
         18 . The system of  claim 1 , wherein the moiety is selected from the group consisting of an organometallic group, a nanoparticle, a conjugated aromatic group, and a conductive organic molecule. 
     
     
         19 . The system of  claim 18 , wherein:
 the moiety is the nanoparticle, and   the nanoparticle comprises gold, silver, platinum, magnesium, or titanium nitride.   
     
     
         20 . The system of  claim 18 , wherein:
 the moiety is the organometallic group, and   the organometallic group comprises ferrocene, metal phthalocyanines, ruthenium, osmium, or transition metal organometallic compounds.