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University of Illinois’ Aleksei Aksimentiev on Nanopore Capacitor Sequencing

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Aleksei Aksimentiev
Assistant Professor, Department of Physics
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign
Name: Aleksei Aksimentiev
 
Age: 33
 
Position: Assistant Professor, Department of Physics, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, since August 2005.
 
Experience and Education:
Postdoc, University of Illinois at Urbana-Champaign, 2001-2005; Postdoc, Mitsui Chemicals, Japan, 1999-2001; PhD in chemistry, Institute of Physical Chemistry, Warsaw, Poland, 1999; MSc in physics, Ivan Franko Lviv State University, Ukraine, 1996.
 

 
Aleksei Aksimentiev, a researcher in the department of physics at the University of Illinois at Urbana-Champaign, has been studying DNA molecules passing through nanopores in ultrathin silicon membranes.
 
Last month, he and his colleagues published a molecular dynamics simulation in Nano Letters that suggests it is possible to sequence DNA by measuring the electrostatic field the molecule induces when it moves back and forth in a nanopore that is exposed to a periodically alternating electric field.
 
In Sequence spoke with Aksimentiev a few weeks ago about his findings.
 
What did you do in this simulation, and what is the background of this project?
 
We have a big interdisciplinary project at the University of Illinois at Urbana-Champaign that is sponsored, in part, by a [2004] $1,000 genome grant from the National Institutes of Health. It is a collaboration between Gregory Timp, myself, Jean-Pierre Leburton, Klaus Schulten, and Stephen Sligar. Greg Timp’s group is making a nanopore device, and my group is trying to figure out how to use it.
 
We studied what happens to a single DNA strand when it is driven back and forth through a very small pore in a very small capacitor, a nanopore capacitor. A capacitor means there are at least three layers: two layers that are metal-like and a middle layer that is made of an insulator. The pore is drilled through that sandwich structure using a transmission electron microscope.
 
We modeled the process of DNA translocation through that structure when it is driven by an alternating electric field. Basically, we are trying to push DNA through a very narrow pore where it would not enter without an electric field that drives it through. We apply an alternating electrostatic potential somewhere away from the capacitor structure and record the voltage that the electrostatic field of DNA induces at the capacitor’s plates.
 
Under such conditions, our simulations show that DNA basically moves in steps through the pore. When the next nucleotide approaches the pore’s constriction, it spends some time searching for the right conformation that allows its base to squish through. Therefore, the nanopore acts like a stepper motor. And the time the DNA spends before it finds the right conformation to enter the pore depends on the type of the base that is about to enter. That’s how we think we will be able to determine the sequence.
 
It took a lot of computer power to do these simulations. The fact that we have, on campus, a National Center for Supercomputing Applications helped a lot. The simulations took probably half a year.
 
What are the challenges to turning this into an actual sequencing device?
 
There are basically two challenges. One is not really a challenge but more a manufacturing issue: We have to reduce the size of the capacitor by about a factor of 10. This would be difficult to make, but it is very possible, so there is no problem with that, it just has to be done.
 
The challenge that is more conceptual is how to reduce the noise in the real experiment. What we have demonstrated in theory is assuming that we can overcome the noise issue.
 
What are the main sources of noise? The random motion of DNA?
 
The conformational noise of DNA is already taken into account in our simulations, and we think that the signal that comes about is still sufficient to distinguish between different types of nucleotides.
 
The noise sources that could cause problems are parasitic capacitances in the semiconductor structure, stochastic motion of ions and water, and some kind of absorption events at the surface of the pore.
 
Our next step would be to take into account all those noise sources into a simulation, and see how we can minimize them by designing a pore better.
 
What is the main difference between your approach and that of other groups working on nanopore sequencing?
 
The main difference is that in our approach, we use a nanopore capacitor, a multi-layered membrane which is made using conventional silicon nanotechnology.
 
Because it is all made of silicon, we can integrate our pore with a signal amplifier. And we can make massively parallel arrays of such pores with ease, so we can scale up very easily. You can imagine making an integrated chip with many, many pores and integrated electronics.
 
Also, we aim to determine the sequence of DNA by measuring the electrostatic potential that the DNA induces in the capacitor, whereas other groups measure either the current that is blocked by the DNA or some tunneling current through the DNA. In that respect, our approach is quite different.
 
What are the pros and cons of your approach, compared to the others?
 
What is good about our approach is that the structures we talk about can be manufactured. It is a realistic device.
 
But those capacitor structures, the electrodes of the capacitors, are still quite thick. It would be nice to reduce them. But they cannot be reduced to a single atom layer because there would not be enough dopant in the semiconductor to sense the electric field of DNA. However, we can reduce the middle dielectric layer that insulates the two layers of the capacitor to an atomic dimension, so that one can confine a single nucleotide.
 
What is your next goal with respect to experimental results?
 
I think the next goal is to demonstrate detection of the sequence-specific signals experimentally, using, of course, known sequences of DNA.
 
Has anybody else done similar work?
 
In terms of simulations, no. There are several groups working on simulations of DNA translocating through nanopores but I think we are the only group that tries to put DNA through pores that are too small for DNA to enter by itself. And that’s why we see all kinds of interesting conformational transitions, which will translate, hopefully, into a way to determine the sequence of DNA.

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