Electronic Detection of DNA-nicks Using 2D Solid-state Nanopore - - PowerPoint PPT Presentation

Electronic Detection of DNA-nicks Using 2D Solid-state Nanopore Transistor

I use Blue Waters to devise novel 2D nanopore systems for genetic and epigenetic detection Presented by Nagendra Athreya PI: Jean-Pierre Leburton

DNA: The Blue Print of Life

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Tonna, Stephen, Assam El-Osta, Mark E. Cooper, and Chris Tikellis. Nature Reviews Nephrology (2010)

Applications of Decoding the Genome

Personalized Medicine Pharmaceutical Research

Point-of-care Genomic Testing

Nelson MR et. al., Nature Genetics, 47(8):856-60. 2015

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Sequencing Technologies

New target < $100

Nanopore Sequencing is a potential solution

Illumina Sequencer

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Principle of Nanopore Sensing

• δI: Average amplitude
• td : Dwell time
• δt: Waiting time between two events

Wanunu, M. (2012, June). Physics of Life Reviews.

Biological Nanopores Solid-state Nanopores

Oxford Nanopore Technologies

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Towards Electronic Detection of Bio-molecules

Image Courtesy: Bayley, Nature, 467,164-65, 2010

Previous Work

Radenovic Group, EPFL, 2013

1. Tunable sensitivity of detection. 2. Easily integrated into semiconductor 3. Massively parallel detection.

Sheet Current

Leburton Group, UIUC, 2013

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Modeling Ionic Currents using BW Nodes

System Model Molecular Dynamics Simulation (NAMD) DNA Trajectory Ionic Current

MD System Setup

summed over all K+, Cl- ions

Ionic Current Calculations

• A. Aksimentiev, et. al, Biophysical Journal, 2004
• ~500k atoms
• 5-10 Nodes/simulation
• 2-4 weeks/simulation

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Electrostatics of nanopore system

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Modeling Electronic Sheet Currents using BW Nodes

DNA Trajectory Self-Consistent Poisson Equation Solver Potentials induced around pore Electronic Transport Calculations using Non-Equilibrium Green’s Function Formalism/Boltzmann transport Electron Current/Conductance

DNA charge model Transverse Electronic Current Response

• Poisson Solver
• 50 Nodes/simulation
• ~6 hours/job
• Electronic Transport
• ~4000 Nodes!!!
• ~6 hours/job

DNA-nick Detection in 2D Nanopore Membranes

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• Human Cell is subjected to ~70,000 lesions/day. Majority of them

arise from DNA backbone breaks.

• These breaks in critical gene cause the cell to undergo apoptosis.
• Contrarily, if repair mechanism fails, the DNA breaks cause

chromosomal instability leading to tumorigenesis.

• No existing technology can efficiently detect these DNA-nicks.
• Our efforts are directed towards unraveling the potential of Two-

dimensional solid-state nanopore membranes to detect and map these site-specific nicks along the genome with single-base resolution.

Site of the nick: A-A

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Potential Profile of Damaged dsDNA translocation

SITE OF THE DNA DAMAGE CURRENT TRACES

T-T C-C G-G

Site Specificity of the nick positions

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Not recognizable by ionic currents

Voltage (Vcis-Trans) dependence

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Normal translocation Denaturing of the DNA

Voltage (Vcis-Trans) dependence

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Breaking point!

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Future Work

§ Cross-base pairs (A-C, A-G, A-T, C-G, C-T, T-G)

§ Different electrically active 2D materials: § Complete voltage dependence analysis

Semi-conductor (MoS2)

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ACKNOWLEDGEMENTS

Jean-Pierre Leburton & Aditya Sarathy Olgica Milenkovic

THANK YOU

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Appendix

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Multigrid Solution of Semiconductor PBE

FMV cycle

Multigrid gives O(N) performance

𝛼 · ) 𝜁(𝐬)𝛼𝜒(𝐬 = −𝑓 ) 𝐿,(𝐬, 𝜒) − 𝐷𝑚0(𝐬, 𝜒 − 𝜍234 − 𝜍56 𝐿,(𝐬, 𝜒) = 𝐷7𝑓

089 :;<

𝐷𝑚0(𝐬, 𝜒) = 𝐷7𝑓

89 :;<

] 𝜍56(𝐬) = 𝑓[𝑂2

,(𝐬) − 𝑂 4 0(𝐬) + 𝑞(𝐬) − 𝑜(𝐬)

𝑞(𝐬) = 𝑂C 2 𝜌 𝐺 ⁄

H I

−𝑓𝜒(𝐬) − 𝐹K 𝑙M𝑈 𝑜(𝐬) = 𝑂6 2 𝜌 𝐺 ⁄

H I

𝐹K + 𝑓𝜒(𝐬) + 𝐹OPQ 𝑙M𝑢 Half Order Fermi-Dirac Function Need to solve 3D Poisson Boltzmann Equation with Newton Multigrid

Gracheva, Maria E., et al. "Simulation of the electric response of DNA translocation through a semiconductor nanopore–capacitor." Nanotechnology17.3 (2006): 622.

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Graphene Nanopore Sheet Conductance Model

Graphene honeycomb lattice Tight-binding Hamiltonian Non-Equilibrium Green’s Function Landauer-Buttiker Formula

Conductance

• A. Girdhar, C. Sathe, K. Schulten, and J. P. Leburton PNAS (2013)

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Graphene Nanoribbon Transverse Conductance

Non-equilibrium Green's function (NEGF)

G: Transverse conductance of the sheet; T(E): Transmission coefficient

f(E): Fermi-Dirac distribution

Conductance (G) Fermi Energy (eV)

Transmission T(E) Carrier Energy (eV)

𝐻1 𝐻1𝐷 𝐻𝐷1 𝐻𝐷 = 𝐹 + 𝑗η W 𝑱 − 𝐼1 𝑊1𝐷 𝑊𝐷1 𝐹 + 𝑗η W 𝑱 − 𝐼𝐷

0H

𝐽 = 2𝑓 ℎ ]

^ ^

W 𝑈 (𝐹)[𝑔

H(𝐹) − 𝑔 I(𝐹)]𝑒𝐹

𝛵 = 𝑊

H6 b

𝐹 + 𝑗η W 𝑱 − 𝐼1 0H𝑊

6H

Fisher-Lee Relation

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All-atom MD Simulations

Current blockade is stronger for lower applied bias!

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Detection of DNA molecule: Ionic Currents

• C. Sathe, X. Zou, J. P. Leburton, and K. Schulten. ACS Nano 2011.

2 nm 7 nm Note the sharp non-linear potential profile!

60 80 20 40 60 80 100 120 140

Diameter (nm)

20 40 0.5 1 1.5 2 2.5 3 60 80 20 40

z (Å) x (Å) (V)

b c Potential profile 4.3 V 2.5 V 0.8 V

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Detecting Stepwise ssDNA Translocation

Conductance in the 2D Membranes due to change in electrostatic potential

0.88 0.90 0.92 0.94 10 20 30 40 2 4 6 8 10 Sheet current (nA) Permeated bases (#) Simulation time (ns)

1 2 3 4

• H. Qiu A. Sarathy, J-P Leburton and K. Schulten Nanoletters (2015)

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Large Scale Parallel DNA Detection in Multi-pore Systems

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Large Scale Parallel DNA Detection in Multi-pore Systems

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