A rapid and low-cost method to sequence DNA would usher in a revolution in medicine. We propose and theoretically show the feasibility of a protocol for sequencing based on the distributions of transverse electrical currents of single-stranded DNA while it translocates through a nanopore. Our estimates, based on the statistics of these distributions, reveal that sequencing of an entire human genome could be done with very high accuracy in a matter of hours without parallelization, e.g., orders of magnitude faster than present techniques. The practical implementation of our approach would represent a substantial advancement in our ability to study, predict and cure diseases from the perspective of the genetic makeup of each individual.Recent innovations in manufacturing processes have made it possible to fabricate devices with pores at the nanometer scale [1][2][3][4][5], i.e., the scale of individual nucleotides. This opens up fascinating new venues for sequencing DNA. For instance, one suggested method is to measure the so called blockade current [6][7][8][9][10][11][12][13][14][15][16][17][18][19]. In this method, a longitudinal electric field is applied to pull DNA through a pore. As the DNA goes through, a significant fraction of ions is blocked from simultaneously entering the pore. By continuously measuring the ionic current, single molecules of DNA can be detected. Other methods using different detection schemes, ranging from optical [20] to capacitive [21], have also been suggested. Despite much effort, however, single nucleotide resolution has not yet been achieved [22].In this Letter, we explore an alternative idea which would allow single-base resolution by measuring the electrical current perpendicular to the DNA backbone while a single strand immersed in a solution translocates through a pore. To do this, we envision embedding electrodes in the walls of a nanopore as schematically shown in the inset of Figure 1. The realization of such a configuration, while difficult to achieve in practice, is within reach of present experimental capabilities [1][2][3][4][5]. The DNA is sequenced by using the measured current as an electronic signature of the bases as they pass through the pore. We couple molecular dynamics simulations and quantum mechanical current calculations to examine the feasibility of this approach. We find that if some control is exerted over the DNA dynamics, the distributions of current values for each nucleotide will be sufficiently different to allow for rapid sequencing. We show that a transverse field of the same magnitude as that driving the current provides sufficient control.We first discuss an idealized case of DNA dynamics which sets the foundations for the approach we describe. Second, we look at the distributions of transverse currents through the nucleotides in a realistic setting using a combination of quantum-mechanical calculations of current and molecular dynamics simulations of DNA translocation through the pore. We use a Green's function method to calculate the c...

Ionic transport in nanopores is a fundamentally and technologically important problem in view of its occurrence in biological processes and its impact on novel DNA sequencing applications. Using microscopic calculations, here we show that ion transport may exhibit strong nonlinearities as a function of the pore radius reminiscent of the conductance quantization steps as a function of the transverse cross section of quantum point contacts. In the present case, however, conductance steps originate from the break up of the hydration layers that form around ions in aqueous solution. Once in the pore, the water molecules form wavelike structures due to multiple scattering at the surface of the pore walls and interference with the radial waves around the ion. We discuss these effects as well as the conditions under which the step-like features in the ionic conductance should be experimentally observable.Over the last decade there have been tremendous advances in both the fabrication of nanopores and their use for molecular recognition and nucleic acid analysis [1]. Experimental characterization of molecules has mostly relied on measuring changes in the ionic current through the pore [2-5], but other ways to probe single molecules in nanopores may come from embedding nanoscale sensors within the pore or nanochannels [6][7][8][9][10][11][12][13]. However, electronic fluctuations due to the dynamical ionic and aqueous environment will affect the type of signals and noise these sensors detect. Therefore, understanding the electrostatics of ions in water at atomic length scales is crucial in our ability to design functional single-molecule sensors and to interpret their output, and will also provide new insight into the operation of the ubiquitous biological ion channels.Several studies have examined the electrostatics of ions in nanopores using continuum models for the dielectric properties of water [14][15][16][17]. Within a continuum model, the nanopore electrostatic environment is essentially one-dimensional due to the large difference of dielectric constants between water and the surrounding pore material [16]. Thus, according to these models, there is a large electrostatic energy penalty to move an ion from the exterior of the pore to its interior [14,16], with small amounts of surface charge able to drastically reduce this energy penalty [14]. Although continuum models can highlight some generic features of ionic currents and blockades, such as the effect of surface charges, they miss important effects related to the microscopic physical structure of water molecules around ions.Here, we examine ionic transport from the point of view of these nanoscale features (see schematic in Fig. (1)). Using all-atom molecular dynamics simulations, we calculate the structural and electrostatic details of a single ion in an aqueous environment both in and out of a cylindrical nanopore (see Methods for details). Ions in solution create local structures in the surrounding water, known as hydration layers [18], and characteri...

We study theoretically the feasibility of using transverse electronic transport within a nanopore for rapid DNA sequencing. Specifically, we examine the effects of the environment and detection probes on the distinguishability of the DNA bases. We find that the intrinsic measurement bandwidth of the electrodes helps the detection of single bases by averaging over the current distributions of each base. We also find that although the overall magnitude of the current may change dramatically with different detection conditions, the intrinsic distinguishability of the bases is not significantly affected by pore size and transverse field strength. The latter is the result of very effective stabilization of the DNA by the transverse field induced by the probes, so long as that field is much larger than the field that drives DNA through the pore. In addition, the ions and water together effectively screen the charge on the nucleotides, so that the electron states participating in the transport properties of the latter ones resemble those of the uncharged species. Finally, water in the environment has negligible direct influence on the transverse electrical current.

In a recent paper, Zikic et al. ͓Phys. Rev. E 74, 011919 ͑2006͔͒ present first-principles calculations of the DNA nucleotides' electrical conductance. They report qualitative and quantitative differences with previous work, in particular with that of Zwolak and Di Ventra ͓Nano Lett. 5, 421 ͑2005͔͒ and Lagerqvist et al. ͓Nano Lett. 6, 779 ͑2006͔͒. In this comment we address the alleged discrepancies, showing that they come from a misrepresentation of our research. Further, we discuss in more detail the issue of geometric fluctuations previously investigated by us, and raised again in the work of Zikic et al. Recently, Zikic et al. ͓1͔ report the conductance of passivated DNA nucleotides located in between nanoscale gold electrodes using density-functional theory ͑DFT͒ within the known exchange-correlation ͑XC͒ functionals. In several places throughout their paper, they compare their findings with previously published results by us ͓2,3͔, and conclude that there are both qualitative and quantitative differences with their work. We point out that Zikic et al. misrepresent the existing literature by leaving out important details, and, further, make comparisons that are at odds with their own approach and conclusions. Also, some comments in their work raise general questions about the adequacy of static approaches to transport and the differences between such approaches. We address these issues below.Zikic et al. correctly state that the electronic signature of nucleotides is strongly dependent on what they call "geometrical factors." Their work is an explicit demonstration of a well-known concept: the tunneling current depends exponentially on the width of the tunneling barrier, which is here formed by the reduced coupling between the electrodes and the nucleotide. For the case of DNA between electrodes, this means that changes in nucleotide orientation modify their coupling to the electrodes, and therefore can drastically change the electrical conductance. In addition, if one fixes the sugar-phosphate backbone position, the different sizes and geometries of the bases will cause them to be more or less close to the electrodes, and therefore cause a difference in their relative conductance. Zikic et al. seem to indicate that these conclusions are qualitatively and quantitatively different from ours. Instead, we understood this fact and we stated explicitly in Ref. ͓2͔ that "͓how well the highest occupied ͑HOMO͒ and lowest unoccupied molecular orbital ͑LUMO͔͒ states couple to both electrodes determines the overall magnitude of the relative currents ͓between the bases͔." In addition, well prior to their work, recognizing the importance of geometrical factors, we explored this issue in much more detail by investigating realistic structural fluctuations in Ref. DFT calculations give what they call mutually consistent results with different exchange-correlation functionals. By mutually consistent they mean that the ordering of the current magnitudes is the same regardless of the XC functional used. Consistency may hold tr...