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Nanopore

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From Molecupedia, the encyclopedia of very small things
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Pore of nanometer size used to detect single molecules by the ionic current through it
This article is about single pores used as sensors. For the sequencing technique, see Nanopore sequencing.
Nanopore sensing
Cross-section of two chambers of salt solution, cis above and trans below, separated by a membrane with one pore; an Ag/AgCl electrode in each chamber wired to a voltage source V and an ammeter A; positive and negative ions moving in opposite directions; a DNA strand entering the pore from cis
A membrane with one pore separates two chambers of salt solution. A voltage drives ions through the pore, and a molecule inside it lowers the current for as long as it stays.
ClassificationResistive pulse sensing; single-molecule electrophysiology
AnalytesIons, DNA, RNA, peptides, proteins, viruses, nanoparticles
Year1996 (single strands of DNA and RNA)
RelatedCoulter counter, Patch clamp, Nanopore sequencing

A nanopore is a hole between about one and a hundred nanometers across, through a thin membrane that separates two chambers of electrolyte, used to detect molecules one at a time. A voltage across the membrane drives an ionic current through the pore. A molecule that enters the pore displaces part of the conducting solution and changes the current for as long as it is inside, so that each passage appears as a brief step in the trace, usually downward, called a current blockade. The depth of the step and its duration carry information about the molecule's size and charge, its shape carries information about its structure, and in the most refined form the series of steps reports the sequence of its subunits.

The measurement is the Coulter principle reduced by four to five orders of magnitude. Wallace Coulter counted blood cells through an aperture tens of micrometers wide in the late 1940s; in 1996 a protein pore 1.4 nm wide at its narrowest point detected single strands of RNA and DNA; and in 2014 sequencers built on engineered protein pores reached their first users. Pores are classed by what they are made of. Biological nanopores are protein channels set in lipid or polymer membranes; solid-state nanopores are holes in thin films of silicon nitride or other materials, in sheets one atom thick, or at the tips of pulled glass capillaries; and mechanical nanopores are pores whose size can be changed while they are in use.

Nanopores are used for sequencing DNA and RNA with long reads, detecting chemical modifications of bases, reading peptides and proteins, mapping genomes, counting viruses and particles, and studying how single molecules fold, stretch and unzip. The main open problems are physical. A molecule driven by the field crosses a pore far faster than electronics can resolve its parts, the currents involved are picoamperes to nanoamperes, solid-state pores are hard to make reproducibly, and any pore can clog, dry out or trap a bubble.

Principle

A current trace that holds a flat level and drops in three short rectangular steps of different depths and widths, with the depth labelled ΔI and the width labelled dwell time
A schematic current trace. The open pore carries a steady current; each passing molecule lowers it by ΔI for its dwell time. Deeper steps come from molecules that fill more of the pore.

A nanopore experiment needs four things: an insulating membrane with one pore in it, an electrolyte on both sides, usually 1 M potassium chloride, a pair of electrodes, usually silver coated with silver chloride, and an amplifier that holds a voltage of about 100 to 200 mV across the membrane while it measures the current. The two chambers are called cis, where the sample is added, and trans. Because the pore is the only conducting path through the membrane, nearly all of the circuit's resistance lies in it and in the small volume of solution at its mouths, and the current reports on that volume alone.

With nothing in it, the pore carries an open-pore current. One alpha-hemolysin channel in 1 M potassium chloride carries about 120 pA at 120 mV, a conductance of 1 nS.[1] A solid-state pore 5 nm wide through a membrane 10 nm thick, in the same solution, is predicted to carry 3.1 nA at 200 mV, or about nineteen billion elementary charges a second.[2][a] At any moment that pore holds about 240 ions, and each spends roughly ten nanoseconds inside. A pore 2 nm wide in a sheet 1 nm thick holds about four.

A molecule that enters the pore excludes ions from part of its volume, and the current falls. In the simplest estimate the fractional drop equals the fraction of the pore's cross-section that the molecule fills: double-stranded DNA, about 2.2 nm wide, would block (2.2/5)2, or 19%, of a pore 5 nm wide. Measured blockades in solid-state pores are smaller than this estimate and shrink further as pores get wider.[2] The step lasts for the dwell time, from microseconds for a short strand in a solid-state pore to seconds for a strand held back by an enzyme. A long DNA molecule that enters folded over on itself gives a step of roughly double depth for part of its passage. At low salt concentration the same molecule can raise the current instead, because the counterions it carries add to the conducting charge; nanopore researchers therefore speak of ionic current modulation as well as blockade.[3]

The passage itself is called translocation. A charged molecule diffuses toward the pore until it comes close enough for the field near the mouth to capture it, threads in, is pulled across by electrophoresis and the flow of water that the ions drag along with them, and leaves on the far side. An experiment records thousands of such events, and much of the science lies in the statistics of their depths, durations and arrival times.

History

Main article: History of nanopore sequencing

Coulter demonstrated the counting of blood cells through a hole in a cellophane wrapper on October 16, 1948, and his patent of 1953 described counting particles by the current pulses they cause in a small aperture.[4] In 1970 Ralph DeBlois and Charles Bean sized polystyrene spheres 90 nm across with single submicron pores etched in irradiated plastic.[5] The patch clamp, with which Erwin Neher and Bert Sakmann recorded the current of single ion channels in 1976, gave biophysicists amplifiers that could resolve picoamperes.[6] In 1994 a group at the National Institutes of Health counted polyethylene glycol molecules passing through a single channel, in a paper that opens with the Coulter counter.[7]

The idea of reading DNA this way is usually traced to a page in David Deamer's notebook dated June 25, 1989, which he filled in red ink after it came to him on a drive through a forested part of Oregon.[8][9] A patent application naming George Church, Deamer, Daniel Branton, Richard Baldarelli and John Kasianowicz was filed in 1995 and granted in 1998.[10] In November 1996 Kasianowicz, Eric Brandin, Branton and Deamer reported that an electric field could drive single strands of RNA and DNA through alpha-hemolysin, a toxin of Staphylococcus aureus, with each passage appearing as a transient decrease of current whose duration was proportional to the length of the strand.[1] The account of who thought of what first is disputed in print, and is given in the article on the history of the field.

Solid-state pores followed in 2001, when a group at Harvard sculpted a pore in silicon nitride with a low-energy ion beam and registered single DNA molecules through it.[11] Oxford Nanopore Technologies was founded in 2005. In 2012 groups at the University of California, Santa Cruz and the University of Washington used a DNA polymerase to step strands through engineered protein pores at 5 Å a step, slow enough to read the bases.[12][13] The first MinION sequencers went to users in June 2014.[8] In 2021 a single peptide was read 117 times in a protein pore.[14]

Types

Biological

Main article: Biological nanopore

Biological nanopores are protein channels, most of them taken from bacterial toxins and transport proteins and assembled from seven to twelve identical subunits. Every pore in a preparation has the same structure to the atom, which makes their currents reproducible. Alpha-hemolysin is a heptamer whose channel runs 10 nm through the membrane and narrows to 1.4 nm.[15] MspA, a porin of Mycobacterium smegmatis, has a constriction about 1.2 nm wide and no more than 0.6 nm long, and mutants with its negative charges removed detect single strands of DNA.[16] Engineered versions of CsgG, a protein that exports the fibres of bacterial biofilms, read DNA in Oxford Nanopore's instruments. Aerolysin, FraC, ClyA and CytK are used for peptides and proteins.

The membrane is the weak part. Lipid bilayers are a few nanometers thick, fragile and short-lived, and Oxford Nanopore's instruments set their pores in synthetic membranes instead.[17] Proteins designed from scratch now add pores that nature did not make: barrels of 10, 12 and 14 strands with conductances of about 110 to 430 pS were reported in 2024.[18]

Solid-state

Main article: Solid-state nanopore

Solid-state pores are holes made in inorganic or polymer membranes, most often silicon nitride films 10 to 50 nm thick on a silicon chip. They tolerate heat, extremes of pH and detergents, can be made at almost any diameter from about 1 nm to many micrometers, and can be built into chips with electrodes and channels. Their surfaces are less well defined than a protein's, no two are quite alike, and they are noisier. Pores have been made in single sheets of graphene and molybdenum disulfide, thinner than any protein pore's constriction; a molybdenum disulfide pore distinguished single nucleotides in 2015.[19][20] Glass nanopipettes, quartz or borosilicate capillaries heated and pulled to a tip tens of nanometers wide, are cheap, quick to make and quieter than most chips.[21][22]

The methods of making them, from electron-beam drilling to controlled dielectric breakdown, are described under nanopore fabrication. Molecular Reality Corporation's public guide summarizes the craft: "A hole this small is an object you build, then photograph, then hope."[23]

Hybrid and DNA-built

A protein pore can be lodged in a solid-state pore to combine the reproducible constriction of the one with the sturdy membrane of the other. In 2010 an alpha-hemolysin pore attached to a strand of DNA was pulled into a silicon nitride pore by the field and stayed there.[24] Pores folded from DNA itself, by the methods of DNA origami, span a wider range of sizes than natural proteins and can be built with chemical groups at chosen positions.

Mechanical and adjustable

Main article: Mechanical nanopore
A small chip glued to the end of a thin rail above a black three-axis positioning stage with red printed parts
A pore chip glued to the tip of a rail above a three-axis micro-positioning stage, from an early sliding-occlusion rig of Molecular Reality Corporation

Most pores are fixed once made. A pore cut in an elastic membrane can be stretched open and allowed to close, a method described in 2007 and sold since 2009 by Izon Science as tunable resistive pulse sensing.[25] Elastomer channels whose cross-section changes reversibly under strain were reported the same year.[26] A pore can also be moved instead of resized: in 2023 a group in Lausanne mounted a glass pore on the probe of a scanning instrument and passed it repeatedly along DNA molecules fixed to a surface, controlling the speed of reading by the motion of the probe.[27]

Molecular Reality Corporation builds rigid pores that change shape by sliding occlusion. Its juxtapore is "a pore formed by two surfaces sliding alongside each other, their edges close enough to form the sensing gap", so that adjusting the surfaces adjusts the gap in real time.[23] The design is described in US patent 10,908,144, granted in 2021 for stacks of coaligned pores in membranes that slide over one another.[28] The company states that it can position the membranes to better than 5 nm; apertures smaller than 15 nm are a target it has not reached.[29]

Physics of the measurement

Conductance

Main articles: Pore conductance and Access resistance

A cylindrical pore of diameter d and length L filled with electrolyte of conductivity σ has a resistance 4L/(πσd2). The current must also converge on the pore from the bulk solution and spread out again on the far side, and this access resistance, which J. E. Hall worked out in a two-page paper in 1975, adds 1/(2σd) on each side.[30] Together they give the conductance

G=σ[4Lπd2+1d]−1,

and measurements on silicon nitride pores 5 to 100 nm wide cannot be fitted without the access term.[2] For the pore 5 nm wide and 10 nm long, the access terms supply more than a quarter of the total resistance. As the membrane gets thinner the first term vanishes and G approaches σd: a pore in graphene is almost all mouth. At low salt concentration, charges on the pore wall attract a cloud of counterions within a Debye length of the surface, and conduction along the wall can rival conduction through the bulk.

Capture and speed

Main articles: Capture rate (nanopore) and Translocation (nanopore)

Outside the pore the field falls off with the square of the distance from the mouth, so a molecule must first diffuse into the region where the field's pull beats its random motion. For a pore of diameter d and length L at voltage ΔV, that region has a radius of about d2μΔV/(8LD), where μ and D are the molecule's electrophoretic mobility and diffusion coefficient. With a twentyfold salt gradient across the membrane, which strengthens the field outside the pore, a silicon nitride pore detected DNA at picomolar concentrations.[31] Below that, transport limits detection. At one femtomolar a microlitre holds about 600 molecules, and most of them would take far longer than any experiment to wander into a pore.[32]

Once captured, a molecule moves too fast. Even the smallest voltage that drives single-stranded DNA through alpha-hemolysin carries each base past the constriction in less than about 1 to 10 µs, while telling one base from another at picoampere currents takes more than 100 µs of signal.[8] The solution in use for DNA is an enzyme bound at the mouth of the pore that feeds the strand through one base at a time, a motor that turns a speeding molecule into a staircase of current levels. A molecule can also be recaptured: reversing the voltage within milliseconds of a passage pulls it back for a second look, and a pore can bounce the same molecule back and forth many times.[33] Two pores in series can hold a strand between them and pull it back and forth, a technique called molecular flossing.

Resolution

The current reports on everything inside the sensing region at once. The stem of alpha-hemolysin is about 5 nm long and holds roughly a dozen bases of a single strand, so each current level is an average over many bases.[8] The much shorter constriction of MspA gave levels that differed by up to 40 pA when a polymerase stepped DNA through it.[13] Sequencing software therefore does not read one base per level. It learns the current produced by each short run of bases, a k-mer, and decodes the sequence from the series of levels, a step called basecalling. Thinner pores in principle read shorter stretches, which is the attraction of membranes one atom thick.

Noise and bandwidth

Main article: Nanopore noise

The current fluctuates for several reasons that dominate at different frequencies. Flicker noise rises toward low frequencies; the pore's thermal noise and the shot noise of the current are flat; and at high frequencies the voltage noise of the amplifier, driven across the capacitance of the chip and wiring, grows in proportion to frequency.[34] Where the last term dominates, the root-mean-square noise grows as the bandwidth to the power 3/2, so making the electronics twice as fast multiplies the noise by about 2.8. Filtering lowers the noise and blurs the short events that carry the information. Two lines of work attack the trade-off: shrinking the capacitance, as with chips on glass below 1 pF, and moving the amplifier onto the same silicon as the pore, which in 2012 resolved events shorter than a microsecond.[35][36] With such electronics, silicon nitride pores 0.8 to 2 nm wide told apart short strands made of a single repeated base at a bandwidth of 1 MHz.[37]

The amplifier itself is a transimpedance amplifier, which converts the current into a voltage through a large feedback resistor or capacitor. A resistor's own thermal noise sets a floor: 1 GΩ contributes about 4 fA/√Hz and 1 MΩ about 130 fA/√Hz, which is one reason picoampere measurements use very large feedback resistances.

Applications

Sequencing

Main article: Nanopore sequencing

In strand sequencing a motor protein ratchets DNA or RNA through a protein pore while the current is recorded, and a neural network translates the current into bases. Reads are as long as the molecules that survive preparation. In 2018 a human genome was assembled from nanopore reads that reached 882 kilobases, and in 2022 ultra-long nanopore reads were among the data used to complete the first gapless sequence of a human genome.[38][39] Because the strand itself passes through the pore, chemical modifications such as methylated cytosine change the current and can be called from the same data, and RNA can be read directly without first copying it into DNA.[40][41] The instruments are small. In 2015 a sequencing laboratory carried to Guinea in airline luggage sequenced Ebola virus samples within 24 hours of receiving them.[42]

Proteins

Main article: Nanopore protein sequencing

Proteins are harder: twenty amino acids instead of four bases, uneven charge along the chain, and folds that must be undone before a chain can thread. An aerolysin pore detected all twenty amino acids attached to a short charged carrier and identified thirteen of them by their blockades.[43] In 2021 a helicase pulled a peptide linked to DNA back and forth through MspA so that one molecule was read 117 times, and combining the reads brought the error in calling a single amino acid change below one in a million.[14] In 2024 an unfolding enzyme moved protein strands hundreds of amino acids long through a pore in steps of about two residues.[44]

Mapping, barcodes and data

Solid-state pores have not read DNA base by base, but they read features along a strand. Two pores in series, with control software that caught and flossed each molecule, mapped the 4.6-megabase genome of Escherichia coli by the positions of tags along its DNA in 2022.[45] DNA carriers built with patterns of bumps along their length act as barcodes that a pore reads in a single passage; a 3-bit barcode was assigned with 94% accuracy in 2016, and the same method detected four antibodies at once.[46] In 2020 a group at Cambridge used the method as rewritable storage: it encoded the word CAMBRIDGE in a DNA structure, erased it and wrote CAVENDISH in its place.[47]

Particles and viruses

Main article: Virus detection with nanopores

Pores tens to hundreds of nanometers wide count and size nanoparticles, vesicles and viruses in the manner of a Coulter counter. In 2018 a group at Osaka University classified single influenza virions in a silicon nitride pore by the shapes of their current pulses, with 68% accuracy for one virion and more than 95% when the pulses of more than 20 were pooled. In 2021 the approach told apart four coronaviruses of similar size and detected SARS-CoV-2 in saliva with 90% sensitivity and 96% specificity in a five-minute measurement.[48][49] A particle can be passed back and forth through a glass pore thousands of times; in 2015 the average of the repeated pulses gave sub-ångström size resolution for particles hundreds of nanometers across.[50]

Signal analysis

Main article: Machine learning on nanopore signals

An experiment produces long current traces sampled hundreds of thousands to millions of times a second. Events are cut out of the baseline, described by features such as depth and dwell time, and classified, or the raw signal is passed to a neural network. Basecalling for sequencing has used hidden Markov models, then recurrent networks, and in the most accurate models that Oxford Nanopore described in 2026, transformers.[51]

Open problems

The speed of an unconstrained molecule, set by the field and the drag of the solution, is the oldest problem, and in biological pores it was solved with motor enzymes that solid-state pores do not have. A solid-state pore reading DNA base by base has not been published; single nucleotides have been told apart in molybdenum disulfide and homopolymers in silicon nitride, but not a sequence read along a strand.[20][37] Reading faster means wider bandwidth and more noise.

The other problems are practical, and most nanopore laboratories meet them daily. Solid-state pores vary from chip to chip and drift over hours. A new pore must be wetted, and a bubble 10 nm across stuck in a hydrophobic pore is held in place by a Laplace pressure of about 28 MPa, close to 300 atmospheres.[52][b] Molecules stick to the walls and clog the pore. Molecular Reality's founder groups these under the name "dumb problems", and names the worst of them: "The biggest, ugliest, dumbest one is: how do you get water through the pore?"[53] His company broke most of a handful of focused-ion-beam pores, bought at about $100 each, in the first week or so of looking for a wetting protocol.[53]

Identification is the last problem. A blockade reports how much of the pore a molecule fills and for how long, and many different molecules can produce the same pulse. Proposed answers include reading the same molecule many times, changing the conditions between reads, attaching labels that a pore can recognize, and teaching networks to separate classes from the full shape of the signal.

Commercial development

Main article: List of nanopore companies

Oxford Nanopore Technologies, founded in 2005 as a spin-out of the University of Oxford, sells sequencers built on engineered protein pores in synthetic membranes, among them the pocket-sized MinION, the Flongle and the high-throughput PromethION.[17] Other companies have worked on protein pores for sequencing or protein analysis, among them Portal Biotech, Qitan Technology and Axbio; on solid-state pores, among them Ontera, formerly Two Pore Guys, Nooma Bio and Aipore; and on related electrical single-molecule methods, among them Quantum Biosystems and Roswell Biotechnologies. Izon Science sells tunable pores for particle analysis. Molecular Reality Corporation, founded in 2018 as demonpore, inc., develops mechanical solid-state pores and streams its measurements on the internet.

See also

Notes

  1. ^ From the model described under Conductance, with a conductivity of 11 S/m for 1 M potassium chloride. A current of 3.1 nA divided by the elementary charge, 1.602 × 10−19 C, is 1.9 × 1010 charges per second, carried by potassium ions moving one way and chloride ions moving the other.
  2. ^ For a bubble of radius 5 nm and the surface tension of water, 0.072 N/m, the Laplace pressure 2γ/r is 2.9 × 107 Pa.

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Further reading

  • Branton, D.; et al. (2008). "The potential and challenges of nanopore sequencing". Nature Biotechnology 26 (10): 1146-1153. doi:10.1038/nbt.1495.
  • Dekker, C. (2007). "Solid-state nanopores". Nature Nanotechnology 2 (4): 209-215. doi:10.1038/nnano.2007.27.
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