dna sequencing via transverse transport: possibilities and
TRANSCRIPT
Massimiliano Di VentraDepartment of Physics, University of California, San Diego
Group
Matt Krems
Yoni DubiH. AppelS. La Fontaine
Former Members
Johan Lagerqvist (London)Mike Zwolak (LANL)Yuriy Pershin (USC)Roberto D’Agosta (Spain)Neil Bushong (NC)Na Sai (U. Texas, Austin)Tony Schindler (UNM)John Gamble (Wooster)Yu-Chang Chen (Chiao Tung U.)Zhongqin Yang (Fudan Univ.)Mairbek Chshiev (UA)
DNA sequencing via transverse transport:possibilities and fundamental issues
M. Zwolak and M. Di Ventra, Physical approaches to DNA sequencing and
detection, Rev. Mod. Phys. 80, 141 (2008).
Outline
� Sequencing via transverse transport
� Quantum transport + Molecular Dynamics
A primer on DNA
Adenine GuanineThymine Cytosine
Backbone
Humans ~ 3 Billion base pairs
• Driven by biased electrodes, DNA can
be analyzed as it translocates a nanopore
Kasianowicz et al Proc. Natl. Acad. Sci. 1996
Pore
Mathe, et al. PNAS 2005
Idea: ionic current in nanopores
α-hemolysin nanopore
Idea: Transverse TransportM
icro
cha
nn
els
Micro
cha
nn
els
FIB Milled Channels
(10-50-nm width)
(a)
AFM Formed Channel
(1-5-nm width and length)
STM Formed Nanoelectrodes
2-nm width
-A-C-T-G-
A C T G
DNAVoltage Biased
translocaton
M. Zwolak and M. Di Ventra,
Nano Lett. 5, 421 (2005)Ramsey et al., unpublished
e-
||Er
⊥Er
Transverse Transport
( )btDNAHE
EGΣ−Σ−−
=1
( ) ( ) ( )[ ]∫ −= EfEfETdEh
eI bt
2
M. Zwolak and M. Di Ventra,
Nano Lett. 5, 421 (2005)
Use ratio of currents as a
measure of their difference
Transverse Transport (static)
0 0.05 0.1Voltage (V)
101
102
103
I A/I
XG
C
T
Electrode Surface
Single Nucleotides
M. Zwolak and M. Di Ventra,
Nano Lett. 5, 421 (2005)
0 0.05 0.1Voltage (V)
101
102
103
I A/I
XG
C
T
Single Nucleotides
M. Zwolak and M. Di Ventra,
Nano Lett. 5, 421 (2005)
Transverse Transport (static)
Transverse Transport (static)
Nearest neighbors
Electrode “size” ~ 1 nm
Transverse Transport (static)
Transverse Transport (static)
Transverse Transport (static)
What about variations of orientation?
Transverse Transport (static)
Transverse Transport (static)
Consider 6 different changes:
Translations:
Rotations:
x y z
x y z
Electrode Surface
Transverse Transport (static)
Transverse Transport (static)
Electrode Surface
100
101
102
103
104
I A/I
X
GC
T
Variations of orientation
Transverse Transport (static)
Noise
• Thermal noise:
V= 1 V; I= 1 nA; ∆f= 10 kHz ⇒ ith= 0.4 pA
• Shot noise:ishot< ith
• 1/f noise:operate at f > 0
• Structural noise
R
fTki Bth
∆=
4
Electronic Noise
Experimental Pores
� Use 4 probes to collect more info (not necessary though)
5 µm
500 nm
Fujimori, et al. Nanotech. 2004.
Molecular Dynamics
� Thousands of atoms
� Full quantum mechanical treatment not possible
NAMD, UIUC
Molecular Dynamics
12.5 Å
25 Å
� Inner diameter 12.5 Å
� Outer diameter 25 Å
� Potassium chloride concentration 1M
� Room Temperature
pore
Top view
E
Molecular DynamicsAdenine
Molecular Dynamics
Adenine
Field effects:� Bending� Stretching
||Er
Transverse Transport (dynamics)
J. Lagerqvist, M. Zwolak, and M. Di Ventra, Nano Letters 2006
Transverse Transport (dynamics)
Transverse Transport (dynamics)
15 bases
Transverse Transport (dynamics)
Driving electric field
� As the field strength increases, the minimum diameter can be decreased
� Decreasing field, bases bend less
0.2x electric field
⊥<< EErr
||
⊥Er
||Er
Controlling the dynamics
J. Lagerqvist, M. Zwolak, and M. Di Ventra, Nano Letters 2006
⊥Er
Current Distributions
{ } ∏∏∏∏
∏∑ ∑
====
=
= +++
=−=N
n
n
G
N
n
n
C
N
n
n
T
N
n
n
A
N
n
n
X
GCTAX PPPP
PX
PError
1111
1
I ,,,n4
1
J. Lagerqvist, M. Zwolak, and M. Di Ventra, Nano Letters 2006
Accuracy 99.9 %
107 measurements/ s
Genome seq. time < 7 hours
No parallelization
Current distributions1 Volt, 12.5 Å spacing
Lagerqvist et al., Nano Lett. 2006
Current distributions1 Volt, 12.5 Å spacing
Lagerqvist et al., Nano Lett. 2006
• Large bias, risk of electrolysiseven though not obvious at nano scale
Current distributions
1 V
Lagerqvist et al., Nano Lett. 2006 Lagerqvist et al., BioPhys. J. 2007
0.1 V
Stabilizing field
Lagerqvist et al., BJ 2007
Adenine, 15 Å spacing
• Stabilizing field helps increase the conductance
Finite bandwidth
Lagerqvist et al., BJ 2007
0.1 V
Finite bandwidth
Lagerqvist et al., BJ 2007
Average:
100 / 1,000 / 10^7 times
Sample at:
10 GHz / 1 GHz / 100 kHz
0.1 V
Effect of probes and environment
1) Electrical probes help distinguish bases due to averaging over configurations
2) Water is not the main source of noise
Without water
With water
3) Main sources of noise: thermal andion fluctuations
� May lead to decoherence
0.1 V
Conclusion: Sequencing protocol
1) Bases can be distinguished statistically if some control is exerted: transverse field.
2) Need to slow down DNA translocation so that more measurements per base can be performed.
⊥<< EErr
||
3) Need to calibrate the device with polybase strands. Re-calibration is probably necessary at intervals of time due to possible atomic rearrangements of the nanopore/electrodes.
References
1) M. Zwolak and M. Di Ventra, Physical approaches to DNA sequencing and detection, Rev. Mod. Phys. 80, 141 (2008).
2) J. Lagerqvist, M. Zwolak, and M. Di Ventra, Influence of the environment and probes on rapid DNA sequencing
via transverse electronic transport, Biophys. J. 93, 2384 (2007).3) J. Lagerqvist, M. Zwolak, and M. Di Ventra, Comment on “Characterization of tunneling conductance across
DNA bases”, Phys. Rev. E 76, 013901 (2007).4) J. Lagerqvist, M. Zwolak, and M. Di Ventra, Fast DNA sequencing via transverse electronic transport, 6, 779
(2006).5) M. Zwolak and M. Di Ventra, Electronic signature of DNA nucleotides via transverse transport, Nano Lett. 5,
421 (2005).
Thanks