Modeling the Biological Nanopore Instrument for Biomolecular State Estimation

The nanopore is a powerful tool for probing biomolecular interactions at the single-molecule level, and shows great promise commercially as a next-generation deoxyribonucleic acid (DNA) sequencing technology. Coupling active voltage control with the nanopore has expanded its capabilities, for example, by allowing precise manipulation of DNA-enzyme complexes at millisecond timescales. However, any change in voltage excites capacitance in the system and results in masking the molecule's contribution to the measured current. To improve active control capabilities, a method is needed for continuous monitoring of the molecule's contribution to the current during voltage-varying experiments. The method must be able to separate the capacitive effects from the channel conductance, which is the parameter that can be used to infer the state of the molecule in the pore. The contributions of this paper are: 1) to develop a dynamic model of the nanopore instrument which includes capacitance and conductance parameters and 2) to develop model-based algorithms for estimating the conductance parameter during voltage varying experiments. First, grey- and black-box state-space models are estimated and compared using nanopore experimental data and system identification tools. Next, a validated grey-box model is used to derive two methods for estimating the channel conductance under voltage-varying conditions: one based on least-squares, and one based on the extended Kalman filter. In simulations and experiments, the Kalman filter outperforms the simpler least-squares method.

[1]  Daniel R. Garalde,et al.  Mapping the position of DNA polymerase-bound DNA templates in a nanopore at 5 A resolution. , 2009, ACS nano.

[2]  D. Branton,et al.  The potential and challenges of nanopore sequencing , 2008, Nature Biotechnology.

[3]  D. Branton,et al.  Microsecond time-scale discrimination among polycytidylic acid, polyadenylic acid, and polyuridylic acid as homopolymers or as segments within single RNA molecules. , 1999, Biophysical journal.

[4]  R S Brody,et al.  Processivity and kinetics of the reaction of exonuclease I from Escherichia coli with polydeoxyribonucleotides. , 1986, The Journal of biological chemistry.

[5]  Andre Marziali,et al.  Noise analysis and reduction in solid-state nanopores , 2007 .

[6]  K. Lieberman,et al.  Specific nucleotide binding and rebinding to individual DNA polymerase complexes captured on a nanopore. , 2009, Journal of the American Chemical Society.

[7]  Mark Akeson,et al.  Replication of Individual DNA Molecules under Electronic Control Using a Protein Nanopore , 2010, Nature nanotechnology.

[8]  G. Goodwin,et al.  High-speed digital signal processing and control , 1992, Proc. IEEE.

[9]  M. Niederweis,et al.  Reading DNA at single-nucleotide resolution with a mutant MspA nanopore and phi29 DNA polymerase , 2012, Nature Biotechnology.

[10]  Ryan J. White,et al.  Simultaneous alternating and direct current readout of protein ion channel blocking events using glass nanopore membranes. , 2008, Analytical chemistry.

[11]  K. Lieberman,et al.  Processive replication of single DNA molecules in a nanopore catalyzed by phi29 DNA polymerase. , 2010, Journal of the American Chemical Society.

[12]  Elizabeth Pennisi,et al.  Genome sequencing. Search for pore-fection. , 2012, Science.

[13]  William B. Dunbar,et al.  Least-squares Estimation of Nanopore Channel Conductance in Voltage-varying Experiments , 2012, BIOSIGNALS.

[14]  Bert Sakmann,et al.  The extracellular patch clamp: A method for resolving currents through individual open channels in biological membranes , 1978, Pflügers Archiv.

[15]  Daniel R. Garalde,et al.  Distinct Complexes of DNA Polymerase I (Klenow Fragment) for Base and Sugar Discrimination during Nucleotide Substrate Selection* , 2011, The Journal of Biological Chemistry.

[16]  R. Bashir,et al.  Nanopore sensors for nucleic acid analysis. , 2011, Nature nanotechnology.

[17]  Mark Akeson,et al.  Automated Forward and Reverse Ratcheting of DNA in a Nanopore at Five Angstrom Precision1 , 2012, Nature Biotechnology.

[18]  Hugh E. Olsen,et al.  Rapid discrimination among individual DNA hairpin molecules at single-nucleotide resolution using an ion channel , 2001, Nature Biotechnology.

[19]  Mark Bates,et al.  Dynamics of DNA molecules in a membrane channel probed by active control techniques. , 2003, Biophysical journal.

[20]  James L. Rae,et al.  Patch voltage clamp of lens epithelial cells: theory and practice , 1984 .

[21]  Amit Meller,et al.  Nanopore force spectroscopy tools for analyzing single biomolecular complexes. , 2010, Methods in enzymology.

[22]  W. Dunbar,et al.  Measuring single-molecule DNA hybridization by active control of DNA in a nanopore. , 2011, Biophysical journal.

[23]  Johnf . Thompson,et al.  Single-molecule DNA analysis. , 2010, Annual review of analytical chemistry.

[24]  B. Sakmann,et al.  Single-Channel Recording , 1983, Springer US.

[25]  William B. Dunbar,et al.  A Kalman filter for estimating nanopore channel conductance in voltage-varying experiments , 2012, 2012 IEEE 51st IEEE Conference on Decision and Control (CDC).

[26]  D. Branton,et al.  Rapid nanopore discrimination between single polynucleotide molecules. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  D. Branton,et al.  Characterization of individual polynucleotide molecules using a membrane channel. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Geoffrey A. Barrall,et al.  Monitoring the escape of DNA from a nanopore using an alternating current signal. , 2010, Journal of the American Chemical Society.

[29]  D. Lingaiah.  Kalman filtering: Theory and practice using MATLAB, 2nd ed [Book Review] , 2003, IEEE Circuits and Devices Magazine.

[30]  D. Deamer,et al.  Sequence-specific detection of individual DNA polymerase complexes in real time using a nanopore. , 2007, Nature nanotechnology.

[31]  H. Bayley,et al.  Continuous base identification for single-molecule nanopore DNA sequencing. , 2009, Nature nanotechnology.

[32]  Amit Meller,et al.  Single molecule measurements of DNA transport through a nanopore , 2002, Electrophoresis.

[33]  Jungsuk Kim,et al.  Recent advances in nanopore sequencing , 2012, Electrophoresis.

[34]  Mark Akeson,et al.  Electronic control of DNA polymerase binding and unbinding to single DNA molecules. , 2009, ACS nano.

[35]  Lennart Ljung,et al.  System Identification: Theory for the User , 1987 .