Ping-pong sensing
| Ping-pong sensing | |
|---|---|
 "Molecular Self-Play", the company's July 2026 animation of an adjustable pore that holds one construct and moves it back and forth through the sensing zone | |
| Classification | Resistive pulse sensing with recapture |
| Analytes | Particles, DNA, proteins |
| Year | 2007 (single DNA molecules); 2015 (nanoparticles) |
| Related | Sliding occlusion, Molecular tomography, Active sensing |
Ping-pong sensing is the repeated measurement of one particle or molecule by driving it back and forth through the sensing zone of a pore. Each pass produces a current pulse, the voltage is reversed after the pass so that the same object comes back, and the pulses are averaged. The uncertainty of the average falls with the square root of the number of passes, so a hundred passes give a tenfold improvement. Molecular Reality Corporation uses the name; its 2022 technical overview says the method is "literally called 'ping-pong' by some workers".[1]
The technique is older than the company and needs no special pore. Fixed solid-state nanopores recaptured single DNA molecules in 2007, and a Coulter counter measured individual nanoparticles thousands of times in 2015. What the company adds is a plan to combine recapture with an adjustable pore, one that could hold a molecule as well as chase it.
Principle
When a particle enters a pore it blocks part of the ionic current, and the depth of the current blockade depends on how much liquid the particle displaces. One pass yields one noisy estimate of that depth. The noise comes from the amplifier, from the pore, and from the particle itself, because Brownian motion changes the path it takes through the aperture. The overview compared the blur to "how faces are blurry in old photographs" and the remedy to "take a hundred photographs, and mathematically reconstruct the faces."[1] If the passes are independent, the standard error of their mean is the single-pass error divided by , so ten thousand passes narrow it a hundredfold.
Recapture has a deadline. When an object leaves the pore, diffusion starts carrying it away from the mouth, and the reversed field must pull it in again before it has gone beyond the distance at which the field dominates. A small molecule with a diffusion coefficient of 10-6 cm2/s moves about 14 nm in the first microsecond and about 140 nm in 100 microseconds, while a large DNA molecule diffuses far more slowly and sits in a field that reaches out over micrometers.[2]
Published work
DNA in fixed pores
Marc Gershow and J. A. Golovchenko reported in 2007 that a double-stranded DNA molecule could be recaptured soon after it had passed through a solid-state pore. A reversal of the voltage within milliseconds sent it back. The measured recapture rates and times fitted a drift-diffusion model. Repeated passes of one molecule improved the accuracy of the measurement, and a molecule could be trapped near the pore and manipulated in solution.[2]
Particles
In 2015 Martin Edwards and colleagues made the case for oversampling in its extreme form. Their Coulter counter used a nanopipette and switched the voltage as soon as it detected a pulse, which reversed the force on the particle and sent it through the orifice again. Each particle was measured more than 100 times a second, and single polystyrene nanoparticles were followed for minutes.[3] The paper's abstract describes a mean blocking current "statistically equivalent to resolving particle radii differing by merely 31 pm". Kemmish's 2026 post on the paper called it "a heroic-effort demonstration of the extremes of oversampling" and noted that 31 pm is "smaller than a single hydrogen atom". He added a caveat: the particles were 250 nm, and it is "much harder to capture and resample smaller analytes by just flipping voltage polarity".[4]
Single molecules, many passes
In 2023 Fei Zheng and colleagues used an asymmetric nanopore that favors recapture on the far side of the membrane. Attaching the target to a long DNA carrier slowed its diffusion, and the same assembly was recaptured more than 100 times, enough to resolve nanostructure motifs along a DNA scaffold.[5] Holding a molecule between two pores is a relative of the same idea. In a 2026 post on molecular flossing Kemmish described it as "just like 'ping-pong', but with tension in the analyte".[6]
Use by the company
The 2022 design of the demonpore 64 console had two selector switches that put a sawtooth on the voltage and a rapid oscillation on the syringe pump, and the overview planned game mechanics around "the player reacting quickly enough to capture and ping-pong individual analytes with translocation profiles on the order of 100s of milliseconds". For small analytes and pores, "automated triggers onboard with the microcontroller" would take over from the player.[1] The overview set ping-pong against a second problem that outlasts the first, the speeding bullet problem: "Even if you can slow things down, they bounce around too much just from getting bumped by water molecules." It listed the method among the forms of translocation control, next to sliding occlusion.
The members' help file defines the term as "using rapidly reversing electrical fields to pull a single molecule back and forth through the nanopore's sensing zone multiple times". It credits the averaging with a better signal-to-noise ratio and says the method "extends observation times to catch rare conformational changes".[7] In July 2026 the company's page on Molecular Self-Play put the idea into a closed loop: a pore "traps a single construct, ping-pongs the analyte through the sensing zone to tomographically sub-sample different conformations, then releases it".[8] Reading one molecule under changed conditions, rather than under the same one, is the subject of molecular tomography.
Limits
A free molecule leaving a 2 nm pore diffuses away within microseconds, the company's critique of its own machine-learning plans points out, and "recapture probability for small free molecules is abysmal". The critique limits per-molecule ping-pong to molecules that are held: on a tether, between two pores, or in a bridge between them. For everything else it recommends measuring the population: "the distribution confesses, not the molecule."[9] Kemmish's March 2026 post said ping-ponging "may or may not be a central enabler of Universal Molecular Streaming".[4]
The company's proposed way around the diffusion problem is mechanical: a pore "you can widen to admit a molecule, then narrow to hold it, then release". Its field guide calls that "the plan" and says it flags it as a plan.[10]
See also
References
- ^ a b c Kemmishtree (March 28, 2026). "2022 sci-tech overview". EQBio-OS.
- ^ a b Gershow, Marc; Golovchenko, J. A. (2007). "Recapturing and trapping single molecules with a solid-state nanopore". Nature Nanotechnology 2 (12): 775-779. doi:10.1038/nnano.2007.381.
- ^ Edwards, Martin A.; German, Sean R.; Dick, Jeffrey E.; Bard, Allen J.; White, Henry S. (2015). "High-speed multipass Coulter counter with ultrahigh resolution". ACS Nano 9 (12): 12274-12282. doi:10.1021/acsnano.5b05554. PMID 26549738.
- ^ a b Kemmishtree (March 28, 2026). "Molecular Supreme". EQBio-OS.
- ^ Zheng, Fei (2023). "DNA carrier-assisted molecular ping-pong in an asymmetric nanopore". Nano Letters 23 (23): 11145-11151. doi:10.1021/acs.nanolett.3c03605.
- ^ Kemmishtree (March 29, 2026). "Flossing with DNA". EQBio-OS.
- ^ "Frequently asked questions". EQBio-OS. Molecular Reality Corporation. 2026.
- ^ "Molecular Self-Play: MSP". Molecular Reality Corporation. July 2026.
- ^ "Keltar's Critique v2: The Nanopore World Model (Hardened)". Molecular Reality Corporation. August 2026.
- ^ "Keltar's Field Guide to Molecular Reality". Molecular Reality Corporation. August 2026.