Abstract
Sequencing by tunneling is a next-generation approach to read single-base information using electronic tunneling transverse to the single-stranded DNA (ssDNA) backbone while the latter is translocated through a narrow channel. The original idea considered a single pair of electrodes to read out the current and distinguish the bases [1, 2]. Here, we propose an improvement to the original sequencing by tunneling method, in which \(N\) pairs of electrodes are built in series along a synthetic nanochannel. While the ssDNA is forced through the channel using a longitudinal field it passes by each pair of electrodes for long enough time to gather a minimum of \(m\) tunneling current measurements, where \(m\) is determined by the level of sequencing error desired. Each current time series for each nucleobase is then cross-correlated together, from which the DNA bases can be distinguished. We show using random sampling of data from classical molecular dynamics, that indeed the sequencing error is significantly reduced as the number of pairs of electrodes, \(N\), increases. Compared to the sequencing ability of a single pair of electrodes, cross-correlating \(N\) pairs of electrodes exponentially improves this sequencing ability due to the approximate log-normal nature of the tunneling current probability distributions. We have also used the Fenton–Wilkinson approximation to analytically describe the mean and variance of the cross-correlations that are used to distinguish the DNA bases. The method we suggest is particularly useful when the measurement bandwidth is limited, allowing a smaller electrode gap residence time while still promising to consistently identify the DNA bases correctly.
Similar content being viewed by others
References
Zwolak, M., Di Ventra, M.: Electronic signature of DNA nucleotides via transverse transport. Nano Lett. 5(3), 421–424 (2005)
Lagerqvist, J., Zwolak, M., Di Ventra, M.: Fast DNA sequencing via transverse electronic transport. Nano Lett. 6, 779–782 (2006)
Zwolak, M., Di Ventra, M.: Colloquium : physical approaches to DNA sequencing and detection. Rev. Mod. Phys. 80, 141–165 (Jan 2008)
Eid, J., Fehr, A., Gray, J., Luong, K., Lyle, J., Otto, G., Peluso, P., Rank, D., Baybayan, P., Bettman, B., et al.: Real-time DNA sequencing from single polymerase molecules. Science 323(5910), 133–138 (2009)
Rusk, N.: Torrents of sequence. Nat. Methods 8(1), 44–44 (2010)
Quail, M.A., Smith, M., Coupland, P., Otto, T.D., Harris, S.R., Connor, T.R., Bertoni, A., Swerdlow, H.P., Gu, Y.: A tale of three next generation sequencing platforms: comparison of ion torrent, Pacific Biosciences and Illumina Miseq sequencers. BMC Genomics 13(1), 341 (2012)
Ohshiro, T., Matsubara, K., Tsutsui, M., Furuhashi, M., Taniguchi, M., and Kawai, T.: “Single-molecule electrical random resequencing of DNA and RNA”, Sci. Rep., vol. 2, 2012.
Tsutsui, M., Shoji, K., Taniguchi, M., Kawai, T.: Formation and self-breaking mechanism of stable atom-sized junctions. Nano Lett. 8(1), 345–349 (2008)
Tsutsui, M., Matsubara, K., Ohshiro, T., Furuhashi, M., Taniguchi, M., Kawai, T.: Electrical detection of single methylcytosines in a DNA oligomer. J. Am. Chem. Soc. 133(23), 9124–9128 (2011)
Krems, M., Zwolak, M., Pershin, Y.V., Di Ventra, M.: Effect of noise on DNA sequencing via transverse electronic transport. Biophys. J. 97, 1990–1996 (2009)
Murphy, M., Rasnik, I., Cheng, W., Lohman, T.M., Ha, T.: Probing single-stranded DNA conformational flexibility using fluorescence spectroscopy. Biophys. J. 86(4), 2530–2537 (2004)
Tsutsui, M., Taniguchi, M., Yokota, K., Kawai, T.: Identifying single nucleotides by tunnelling current. Nat. Nanotechnol. 5, 286–290 (2010)
He, Y., Tsutsui, M., Fan, C., Taniguchi, M., Kawai, T.: Controlling DNA translocation through gate modulation of nanopore wall surface charges. ACS Nano 5(7), 5509–5518 (2011)
Ahmed, T., Haraldsen, J., Rehr, J.J., Di Ventra, M., Schuller, I., and Balatsky, A.: Correlation dynamics and enhanced signals for identification of serial biomolecules and DNA bases. Nano. 25, 125705 (2014). doi:10.1088/0957-4484/25/12/125705
Garaj, S., Hubbard, W., Reina, A., Kong, J., Branton, D., Golovchenko, J.: Graphene as a subnanometre trans-electrode membrane. Nature 467, 190–193 (2010)
Huang, S., He, J., Chang, S., Zhang, P., Liang, F., Li, S., Tuchband, M., Fuhrmann, A., Ros, R., Lindsay, S.: Identifying single bases in a DNA oligomer with electron tunnelling. Nat. Nanotechnol. 5, 868–873 (2010)
Phillips, J.C., Braun, R., Wang, W., Gumbart, J., Tajkhorshid, E., Villa, E., Chipot, C., Skeel, R.D., Kale, L., Schulten, K.: Scalable molecular dynamics with NAMD. J. Comput. Chem. 26, 1781–1802 (2005)
Di Ventra, M.: Electrical Transport in Nanoscale Systems. Cambridge University Press, Cambridge (2008)
Pecchia, A., Gheorghe, M., Di Carlo, A., Lugli, P., Niehaus, T.A., Frauenheim, T., Scholz, R.: Role of thermal vibrations in molecular wire conduction. Phys. Rev. B 68, 235321 (Dec 2003)
Mitra, S., Mukhopadhyay, R., Tsukushi, I., Ikeda, S.: Dynamics of water in confined space (porous alumina): Qens study. J. Phys.: Condens. Matter 13, 8455 (2001)
Fenton, L.: The sum of log-normal probability distributions in scatter transmission systems. Commun. Sys. IRE Trans. 8(1), 57–67 (1960)
Acknowledgments
This work was supported in part by the National Institutes of Health, US DOE, AFOSR Project No. FA 9550-10-1-0409, and ERC-DM-321031. A. V. Balatsky acknowledges useful conversations with T. Ahmed, J. Haraldsen, T. Kawai, and M. Taniguchi.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Boynton, P., Balatsky, A.V., Schuller, I.K. et al. Improving sequencing by tunneling with multiplexing and cross-correlations. J Comput Electron 13, 794–800 (2014). https://doi.org/10.1007/s10825-014-0571-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10825-014-0571-2