(462b) DNA Translocation through Nanopores Under Time-Varying Electric Fields: A Brownian Dynamics Study

The single-molecule analysis of biopolymers such as DNA and proteins has a wide range of potential applications in medicine and biotechnology. In particular, devices for high-speed and inexpensive analysis (e.g., sequencing) of biopolymers offer a route towards overcoming the limitations of conventional techniques like electrophoresis. One of the promising single-molecule methods is based on the use of nanopore devices, which are individual porous channels of diameters 1-5 nm and lengths 5-25 nm. Because DNA is negatively charged under usual solution conditions in water, it can be translocated through the nanopore with the aid of an applied electric field. By measuring the translocation time for DNA through the nanopore (usually in the range of ~ 1-10 μs/base) and the modulations in ionic current through the pore caused by the presence of DNA, many characteristics of a DNA chain can be deduced such as the length and the sequence of base pairs.

Among the different types of nanopore devices being used in translocation time measurements, solid state (e.g., silicon nitride) nanopores, have had good success. Nanopore devices are currently operated using DC electric fields and cannot discriminate between biopolymers that differ only slightly in length. In previous work [1] we proposed, using a simple mathematical model, that the application of optimized electric fields would dramatically increase the resolution of the device in successfully discriminating biopolymers that differ only slightly in length. The aim of the present work is to develop insights into the translocation of DNA through nanopores under the application of time-varying electric fields, and to investigate the possibility of improved resolution of nanopore devices by this method.

We will first discuss the development of an accurate Brownian Dynamics model that captures all the essential dynamics associated with DNA translocation through a silicon nitride pore. DNA is modeled as a freely jointed chain using a bead-spring model, with the flexibility to increase the number of DNA monomers per bead and to use two different spring force laws (Fraenkel and Warner). Both the excluded volume effect and the interactions between DNA and the silicon nitride nanopore are modeled with a Lennard-Jones potential using parameters obtained from measured data. To accurately model the electrostatic effects in the system, we compute the potential due to the applied voltage and the charges associated with the atoms of the nanopore by Poisson's equation. The Langevin approach is used for integrating the equations of motion of the DNA chain, leading to the incorporation of stochastic thermal fluctuations into the model.

We then discuss the application of this model to study the transport of DNA in silicon nitride nanopores of diameter 1-5 nm and thickness 5-10 nm under the influence of both direct and time-varying electric fields. We investigate the effects of chain length, composition, and electrolyte conditions upon the translocation properties including the average translocation time and the statistical variance in translocation time due to thermal fluctuation. Using our detail computational method, we rigorously examine our earlier proposition that the use of time-varying electric fields (e.g., sinusoidal and square wave forms) substantially improve the resolution of DNA size analysis using nanopores. In particular, there is a ?resonance effect? that occurs when the frequency of the applied electric field matches the characteristic time scale of the translocation process. We conclude by discussing the implications of our findings for design and operation of nanopore sensors for biomolecular analysis application.

References

[1]. Bhattacharya S., Nair S., Chatterjee A., An Accurate DNA Sensing and Diagnosis Methodology Using Fabricated Silicon Nanopores. IEEE Transactions on Circuits and Systems I: Regular Papers. 2006; 53(11): 2377-2383.