Third Generation DNA Sequencing with a Nanopore - Nanopores: Sensing and Fundamental Biological Interactions - page 307

is an exponent that is typically unity and A R p
Consistent with these observations, Hooge suggested that l/f noise occurs in bulk
conductors due to the fluctuating mobility of charge carriers that produces current
fluctuations [ 44 , 66 , 67 ]. Generally, associated with the coefficient A we find that
g ¼

carriers, f is the frequency, b

1.03 0.44 over a factor of 10,000 in pore resistance, in support of

Hooge's phenomenological picture.
As illustrated in Fig. 12.9b, c , we find that the noise spectrum for f < 100 Hz is

sensitive to the electrolyte concentration, while the high frequency noise is not. 1/f
noise becomes negligible at frequencies f > 1 kHz, and the spectrum exhibits linear
frequency dependence up to about 50 kHz. The linear frequency dependence,
coupled with the lack of a dependence of this part of the spectrum on the electrolyte
concentration, which is evident from Fig. 12.9b, c , indicates dielectric noise with a
spectrum of the form: S D ¼

where D and C m are the loss tangent
and the effective capacitance of the dielectric membrane.
Finally, according to the Fig. 12.9d , the noise in the range 100-50 kHz is the
dominant contribution to the rms-current noise - it is exponentially larger than
the 1/f component. Above 50 kHz, the spectrum is strongly affected by the
bandwidth of the amplifier and interconnections to it. Thus, reducing parasitic
capacitances, electrolyte resistance and amplifier noise are all key elements for
improving both the frequency and noise performance.

4 k B TDC m ð 2 pf Þ;

12.3 Conclusion

A nanopore is an analytical tool with single molecule sensitivity. It operates in a
way that is reminiscent of Coulter's original idea of using dielectric objects
within a constricted current path to alter the electrical resistance [ 68 ]. In this
chapter we have explored both the promise and limitations of using a nanopore
in a solid state membrane for one especially compelling application: sequencing
double-stranded DNA.
It may now be possible to control both the translocation kinetics and the
configuration of double stranded DNA in a pore by controlling the pore geometry.
Semiconductor nanofabrication is a key factor, enabling the creation of structures
with sub-nanometer precision. Leveraging the precision to produce nanopores in a
solid-state membrane smaller in diameter than the double helix,, a single molecule
of double-stranded DNA can be trapped in a pore by applying an electric force
larger than the stretching threshold. Once a current blockade associated with a
translocating molecule is detected, the electric field in the pore is switched in an
interval less than the translocation time to a value below the threshold for stretch-
ing. This leaves the dsDNA stretched in the pore constriction with the base-pairs
tilted, while the B-form canonical structure is preserved outside the pore. In this
configuration, the translocation velocity is substantially reduced to ~1 bp/2 ms
in the extreme, which could allow discrimination between A-T and C-G base-pairs
just by measuring the ionic current.