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Hybrid Biomolecular Electronic Devices Dr Steve Johnson Department of Electronics University of York What is Biomolecular Electronics Hybrid technology focused on the integration, detection and manipulation of biological molecules,

SLIDE 1

Dr Steve Johnson

Department of Electronics

University of York

Hybrid Biomolecular

Electronic Devices

SLIDE 2

What is Biomolecular Electronics

Hybrid technology focused on the integration, detection and manipulation of biological molecules, such as DNA, proteins and peptides with electronic devices

SLIDE 3

Biological molecules primer

guanine cytosine

NH N HN N O NH2 O H2N NH N N N HN N NH2 HN NH O O

adenine thymine

Single stranded DNA

Sugar deoxyribose

ne of the four possible

DNA bases (ACTG) Phosphate group acid part of DNA

DNA bases

2.2nm 1.2nm 1nm

Double stranded DNA

SLIDE 4

Amino acid

Amine Carboxylic acid Side chain variable

Biological molecules primer

Tertiary structure Quaternary structure Primary structure Secondary structure Polypeptide

Peptide bond

SLIDE 5

Molecular recognition: spontaneous assembly of molecules driven by interactions between complementary biomolecules

Biomolecules: beyond biology

DNA tiles: Nadrian Seeman (1982)

e.g. DNA

DNA origami: Paul Rothemund 2006

e.g. proteins & peptides

A. J. Olson: Scripps Research Institute

Video removed: See https://www.youtube.com/watch? v=X-8MP7g8XOE

SLIDE 6

Molecular recognition between complementary biomolecules to store and process information encoded by the polymer sequence

Biomolecules for computation

Why: Parallel processing (10 base DNA = 1×106 distinct sequences; 10 residue peptide = 1×1013)

High selectivity and low error rates - failure to function = death! Cost (synthetic DNA: £1 per base, synthetic peptide: £5 per reside) Integration with biological systems (e.g. smart drugs)

node (i) path (j-i) path (i-k)

DNA-based computing machines Direct hybridisation

Adleman Science, 266, 1021 (1994)

Toe-hold strand displacement

Erik Wilkman J. Am. Chem. Soc. 131, 17303 (2009)

1 2* 3 2 2* 1* 2* 1* 1 2* 3 2 1 2 2* 1* 3 2*

Input Output toe-hold

SLIDE 7

Biomolecules for computation

Strand displacement DNA logic

Frezza JACS, 129, 14875 (2007)

SLIDE 8

Biomolecules for computation

input + clock transition

Molecular machines based on DNA hairpins

Christina Santini et al. Chem. Comms. 49, 237 (2013) fuel/ clock

SLIDE 9

Biomolecules for computation

Protein and peptide-based computing machines

Enzymatic logic

J. Phys. Chem. A. 110, 8548 (2006)

HRP

Horseradish peroxidase

input 1

glucose

input 2

H2O2 NAD+

utput

NADH

GDH

glucose dehydrogenase input 1 input 2

utput

1 1 1 1 1 1 0 XOR logic

Computational machines theorised exploiting antibody-antigen interactions

not yet realised due to lack of appropriate antibodies - synthetic antibody mimetics

Peptide networks

JACS, 126, 11140 (2004)

input1: E3+N input2: E4+N

OR logic

SLIDE 10

Biomolecules for computation: Challenges

Designing (programming) the machine: Particularly challenging for protein/ peptide based devices Reading the output: PCR, gel electrophoresis, fluorescence, mass spectrometry Integrating biological circuits: Incompatibility between input (DNA, peptide, protein, chemical) and output signals (biomolecular, chemical, fluorescent) Hybrid biomolecular electronics:

Direct (label-free) read-out
Integration via underlying electronics

SLIDE 11

Biomolecular electronics: Immobilisation I

Immobilising DNA onto inorganic surfaces Stable, covalent surface attachment via thiol chemistry Thiolated short chain alkanes to present DNA and block exposed Au

DNA − SH + Au → DNA − S − Au + H

S Au SH S Au S S S S S S Au SH

Regulating surface density of DNA Minimise steric hindrance - DNA hairpins

S S S S S S

clock clock

SLIDE 12

Biomolecular electronics: Immobilisation II

Immobilising peptides/ proteins onto inorganic surfaces Pre-assembly of chemoselective, biocompatible monolayer

J. Mat. Chem. B. submitted (2014)

S Au S S S S S S Au S Au S S S S S S

PEG

NH2 SH

Images removed

SLIDE 13

Biomolecular electronics: Immobilisation II

binding region

500 1000 1500 0.0 0.2 0.4 0.6

Time (s) Mass (ng/mm2)

500 1000 1500 0.0 0.1 0.2 0.3

Time (s) (a) (b) ligand binding site

S Au S S S S S S S Au S S S S S S

Protein orientation

Anal. Chem. 80, 978 (2008)

Images removed

SLIDE 14

Biomolecular electronics: Immobilisation III

Immobilising biomolecules with high spatial resolution Peptides: sub-100 nm resolution

Nanotechnology, 23, 495304 (2012) 1µm

DNA: sub-50nm resolution

Langmuir, 19, 981 (2003)

SLIDE 15

Biomolecular electronics: Detection I

mol

10–1 100 101 102 103 104 –80 –60 –40 –20 ϕ(z) (deg) Frequency (Hz)

10–1 101 –80 –70

10–1 100 101 102 103 104 –80 –60 –40 –20 ϕ(z) (deg) Frequency (Hz)

mol

Electrochemical impedance spectroscopy (EIS)

SLIDE 16

Biomolecular electronics: Detection I

Electrochemical impedance spectroscopy (EIS) Cell lysate: i.e. select specific protein out of cocktail of circ. 1M other proteins, DNA, RNA, fats, lipids, salts ...

Detection limit 50pM

SLIDE 17

Biomolecular electronics: Detection II

Cyclic voltammetry: Redox DNA hairpins

2 e- 2 H+

S d

Clock

S d

Images removed

SLIDE 18

Biomolecular electronics: Regulation I

Redox active systems

Langmuir , 28, 6632 (2012)

Eox 6= Ered?

Au Au S C Au O OH S C Au O OH S C Au O OH S C Au O OH Cu2+ Cu2+

e

0.0 0.4 –0.4 –0.2 0.0 0.2 0.4 0.6 Ewe (V) I ( A) Vpk Cu Cu

1 2 3 Thickness (nm) Cu1+ Cu2+ Cu1+ Cu2+ Cu1+ Cu2+ Cu1+

0.8 1.2 Cu2+ Cu1+ 1.5nm 1.9nm

SLIDE 19

Biomolecular electronics: Regulation II

Protein charge sensitive to local solution conditions e.g pH, ionic strength

e.g. pH sensitivity of HA protein of flu virus

Low pH (High H+) High pH (Low H+) Mid-range pH

H+

Images removed