Molecular and atomic scale evaluation of biopolymers
First Claim
1. An apparatus for use in evaluating a linear polymer molecule, comprising:
- a vessel for holding a liquid containing a candidate polymer molecule;
a solid-state membrane containing an aperture therein, said aperture comprising a constraining dimension, wherein the aperture includes an entry port and an exit port defining a channel there between, and wherein the membrane is positioned to be contactable with a liquid in the vessel;
means for causing a candidate polymer molecule to linearly traverse the aperture; and
a detector for detecting sensing time-dependent or monomer-dependent interactions of a candidate molecule with the aperture detector, said detector located in the aperture or on a face of the solid-state membrane.
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Abstract
A method for evaluating a polymer molecule including linearly connected monomer residues includes providing a polymer molecule in a liquid, contacting the liquid with an insulating solid-state membrane having a detector capable of detecting polymer molecule characteristics, and causing the polymer molecule to traverse a limited region of the solid-state membrane so that monomers of the polymer molecule traverse the limit region in sequential order, whereby the polymer molecule interacts linearly with the detector and data suitable to determine polymer molecule characteristics are obtained. The limited region may be defined by a nanometer-sized aperture in the membrane.
439 Citations
76 Claims
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1. An apparatus for use in evaluating a linear polymer molecule, comprising:
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a vessel for holding a liquid containing a candidate polymer molecule;
a solid-state membrane containing an aperture therein, said aperture comprising a constraining dimension, wherein the aperture includes an entry port and an exit port defining a channel there between, and wherein the membrane is positioned to be contactable with a liquid in the vessel;
means for causing a candidate polymer molecule to linearly traverse the aperture; and
a detector for detecting sensing time-dependent or monomer-dependent interactions of a candidate molecule with the aperture detector, said detector located in the aperture or on a face of the solid-state membrane. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
at least one insulating layer adjacent to the first and second electrodes.
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27. The apparatus of claim 1, wherein the apparatus further comprises a monitoring means, and the monitoring means comprises an ammeter or an electrometer.
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28. The apparatus of claim 1, wherein the means for causing a candidate polymer molecule to traverse the aperture is selected from the group consisting of voltage gradient means and biomotors.
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29. The apparatus of claim 1 or 22, further comprising:
a substrate supporting the solid-state membrane.
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30. The apparatus of claim 1, wherein a polymer replicating catalyst is in contact with the aperture.
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31. The apparatus of claim 30, wherein the polymer replicating catalyst is located adjacent to, above, below, or within the membrane aperture.
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32. The apparatus of claim 31, wherein the polymer replicating catalyst is the constraining dimension diameter feature.
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33. The apparatus of claim 1, wherein the detector comprises an electrode pair located on opposing faces of the solid-state membrane, and the detector detects interactions of the electrode pair with a candidate molecule located between the electrode pair, and wherein the constraining dimension located at or between the electrode pair.
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34. The apparatus of claim 33, wherein a detection signal arises from longitudinal electron tunneling along the length of the aperture channel.
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35. The apparatus of claim 1, wherein the detector comprises an electrode pair located on a face of the solid-state membrane spaced apart from one another at opposing sides of the entry port or the exit port of the aperture.
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36. The apparatus of claim 35, wherein the electrode pair comprises the constraining dimension.
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37. The apparatus of claim 33 or 35, wherein the apparatus further comprises a dielectric layer disposed on each of the electrodes of the electrode pair.
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38. The apparatus of claim 35, wherein a detection signal arises from transverse electron tunneling across the aperture.
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39. An apparatus for use in evaluating a linear polymer molecule, comprising:
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a first vessel having a first inlet therein;
a second vessel having a second inlet therein;
an elongated member having first and second ends, each end in sealing communication with the respective inlets of the first and second vessels;
a solid-state membrane containing an electrically insulating aperture therein disposed in the first end of the elongated member, wherein the aperture includes an entry port and an exit port defining a channel there between, and the membrane is positioned to be contactable with a liquid containing a candidate polymer molecule in the first vessel;
means for causing a candidate polymer molecule to linearly traverse the aperture; and
a detector for sensing time-dependent or monomer-dependent interactions of a candidate molecule with the detector, said detector located in the aperture or on a face of the solid-state membrane .
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40. A method for evaluating a polymer molecule, the polymer molecule including linearly connected monomer residues, comprising:
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contacting a liquid containing a polymer molecule with an insulating solid-state substrate having a detector capable of detecting polymer molecule characteristics;
causing the polymer molecule to traverse a limited volume on the solid-state substrate so that monomers of the polymer molecule traverse the limited volume in sequential order, whereby the polymer molecule interacts sequentially with the detector, whereby the detector comprises an electrode pair, and electron current is detected as the monomer traverses the limited volume and data suitable to determine polymer molecule characteristics are obtained. - View Dependent Claims (41, 42, 43, 44, 45, 64, 65, 66, 67)
a polymer replicating catalyst attached to the solid-state surface adjacent to the detector, whereby the polymer molecule is acted upon by the polymer replicating catalyst, so that the polymer molecule interacts sequentially with the detector as it advances through the polymer replicating catalyst.
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44. The method of claim 43, wherein the liquid is a solution further including reagents necessary to replicate the polymer molecule.
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45. The apparatus of claim 40, wherein the constraining dimension is located adjacent to, below, above or within the aperture.
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64. The method of claim 40, 60 or 63, wherein the amplitude of duration of individual conductance measurements is indicative of sequential identity of monomers of the polymer molecule.
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65. The method of claim 40, 60 or 63, wherein the number of changes in the conductance measurement is an indication of the number of monomers in the polymer.
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66. The method of claim 40, 60 or 63, wherein the duration of the individual conductance measurement is an indication of the number of monomers in the polymer molecule.
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67. The method of claim 40, 60 or 63, wherein multiple molecules of a heterogeneous mixture of individual polymer molecules are characterized to provide a size distribution of polymers in the mixture.
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46. A method for evaluating a polymer molecule, the polymer molecule including linearly connected monomer residues, comprising:
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contacting a liquid containing a polymer molecule with an insulating solid-state membrane having an aperture therein, wherein the aperture includes an entry port and an exit port defining a channel there between, causing the polymer molecule to traverse the aperture of the membrane, whereby the polymer molecule interacts sequentially with a constraining dimension in, of or at the aperture and data arising from time-dependent or monomer-dependent interactions of a candidate molecule with a detector located in the aperture or on a face of the solid-state membrane are obtained. - View Dependent Claims (47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 68, 69, 70, 71)
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72. A method for evaluating a polymer molecule, the polymer molecule including linearly connected monomer residues, comprising:
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providing a candidate hybridized polynucleotide molecule in a liquid;
contacting a liquid containing a candidate hybridized polynucleotide molecule with an insulating solid-state membrane having an aperture therein, said aperture having a diameter insufficient to permit traversal of the hybridized molecule of the aperture;
causing the candidate polymer molecule to traverse the aperture of the membrane, whereby the hybridized polymer molecule is denatured and the single-stranded polymer interacts sequentially with the aperture and data suitable to determine polymer molecule characteristics are obtained. - View Dependent Claims (73, 74, 75, 76)
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Specification