Single-molecule Field-effect Transistor Research Articles

Single-Molecule Electrical Profiling of Peptides and Proteins.

In recent decades, there has been a significant increase in the application of single-molecule electrical analysis platforms in studying proteins and peptides. These advanced analysis methods have the potential for deep investigation of enzymatic working mechanisms and accurate monitoring of dynamic changes in protein configurations, which are often challenging to achieve in ensemble measurements. In this work, the prominent research progress in peptide and protein-related studies are surveyed using electronic devices with single-molecule/single-event sensitivity, including single-molecule junctions, single-molecule field-effect transistors, and nanopores. In particular, the successful commercial application of nanopores in DNA sequencing has made it one of the most promising techniques in protein sequencing at the single-molecule level. From single peptides to protein complexes, the correlation between their electrical characteristics, structures, and biological functions is gradually being established. This enables to distinguish different molecular configurations of these biomacromolecules through real-time electrical monitoring of their life activities, significantly improving the understanding of the mechanisms underlying various life processes.

Time-domain event detection using single-instruction, multiple-thread gpGPU architectures in single-molecule biophysical data

Discrete amplitude levels in ordered, time-domain data often represent different underlying latent states of the system that is being interrogated. Analysis and feature extraction from these data sets generally requires considering the order of each individual point; this approach cannot take advantage of contemporary general-purpose graphics processing units (gpGPU) and single-instruction multiple-data (SIMD) instruction set architectures. Two sources of such data from single-molecule biological measurements are nanopores and single-molecule field effect transistor (smFET) nanotube devices; both generate streams of time-ordered current or voltage data, typically sampled near 1 MS/s, with run times of minutes, yielding terabyte-scale datasets. Here, we present three gpGPU-based algorithms to overcome limitations associated with serial event detection in time series data, resulting in a 250× improvement in the rate with which we can detect salient features in nanopore and smFET datasets. The code is freely available.

Carbon-nanotube field-effect transistors for resolving single-molecule aptamer-ligand binding kinetics.

Small molecules such as neurotransmitters are critical for biochemical functions in living systems. While conventional ultraviolet-visible spectroscopy and mass spectrometry lack portability and are unsuitable for time-resolved measurements in situ, techniques such as amperometry and traditional field-effect detection require a large ensemble of molecules to reach detectable signal levels. Here we demonstrate the potential of carbon-nanotube-based single-molecule field-effect transistors (smFETs), which can detect the charge on a single molecule, as a new platform for recognizing and assaying small molecules. smFETs are formed by the covalent attachment of a probe molecule, in our case a DNA aptamer, to a carbon nanotube. Conformation changes on binding are manifest as discrete changes in the nanotube electrical conductance. By monitoring the kinetics of conformational changes in a binding aptamer, we show that smFETs can detect and quantify serotonin at the single-molecule level, providing unique insights into the dynamics of the aptamer-ligand system. In particular, we show the involvement of G-quadruplex formation and the disruption of the native hairpin structure in the conformational changes of the serotonin-aptamer complex. The smFET is a label-free approach to analysing molecular interactions at the single-molecule level with high temporal resolution, providing additional insights into complex biological processes.

Characterizing the Conformational Free-Energy Landscape of RNA Stem-Loops Using Single-Molecule Field-Effect Transistors.

We have developed and used single-molecule field-effect transistors (smFETs) to characterize the conformational free-energy landscape of RNA stem-loops. Stem-loops are one of the most common RNA structural motifs and serve as building blocks for the formation of complex RNA structures. Given their prevalence and integral role in RNA folding, the kinetics of stem-loop (un)folding has been extensively characterized using both experimental and computational approaches. Interestingly, these studies have reported vastly disparate timescales of (un)folding, which has been interpreted as evidence that (un)folding of even simple stem-loops occurs on a highly rugged conformational energy landscape. Because smFETs do not rely on fluorophore reporters of conformation or mechanical (un)folding forces, they provide a unique approach that has allowed us to directly monitor tens of thousands of (un)folding events of individual stem-loops at a 200 μs time resolution. Our results show that under our experimental conditions, stem-loops (un)fold over a 1-200 ms timescale during which they transition between ensembles of unfolded and folded conformations, the latter of which is composed of at least two sub-populations. The 1-200 ms timescale of (un)folding we observe here indicates that smFETs report on complete (un)folding trajectories in which unfolded conformations of the RNA spend long periods of time wandering the free-energy landscape before sampling one of several misfolded conformations or the natively folded conformation. Our findings highlight the extremely rugged landscape on which even the simplest RNA structural elements fold and demonstrate that smFETs are a unique and powerful approach for characterizing the conformational free-energy of RNA.

Enhancing the On/Off Current Ratio in Single-Molecule FET via Destructive Quantum Interference

We investigate through atomistic calculation the electronic structure and transport properties of 3-phenylethynylene (OPE3), 7-phenylvynylene (OPV7), and [3, 3]paraCyclophane (pCp)-based molecules. We reveal and analyze the Destructive Quantum Interference (DQI) phenomenon for the pCp single-molecule junction. The provided explanation of DQI via the dominant concurrence of inter-orbital and intra-orbital interference may support DQI engineering through the chemical synthesis of ad hoc molecular channel. Furthermore, we propose a Back gate Biasing-based method for the ON/OFF CUrrent Ratio Enhancement of the single-molecule Field-Effect transistor via the control of DQI (BBB-CURE-DQI). As an important outcome of the proposed method, an ON/OFF current ratio of 103 is achieved for pCp single-molecule FET. This value is orders of magnitude larger than typical values presented in the literature. The benefit of the DQI and the effectiveness of the BBB-CURE-DQI method are finally demonstrated at the circuital level by SPICE simulations of digital inverters implemented with the investigated molecules. Our analysis and results motivate the importance of future research investment for DQI manipulation via chemical synthesis and successive control to enable single-molecule FET-based nanocomputing applications.

Dual-gated single-molecule field-effect transistors beyond Moore\u2019s law

As conventional silicon-based transistors are fast approaching the physical limit, it is essential to seek alternative candidates, which should be compatible with or even replace microelectronics in the future. Here, we report a robust solid-state single-molecule field-effect transistor architecture using graphene source/drain electrodes and a metal back-gate electrode. The transistor is constructed by a single dinuclear ruthenium-diarylethene (Ru-DAE) complex, acting as the conducting channel, connecting covalently with nanogapped graphene electrodes, providing field-effect behaviors with a maximum on/off ratio exceeding three orders of magnitude. Use of ultrathin high-k metal oxides as the dielectric layers is key in successfully achieving such a high performance. Additionally, Ru-DAE preserves its intrinsic photoisomerisation property, which enables a reversible photoswitching function. Both experimental and theoretical results demonstrate these distinct dual-gated behaviors consistently at the single-molecule level, which helps to develop the different technology for creation of practical ultraminiaturised functional electrical circuits beyond Moore’s law.

Recent progress in single-molecule transistors: their designs, mechanisms and applications

Single-molecule field-effect transistors (FETs) are the key building blocks of electronic circuits and a unique platform for studying physical mechanisms. Here, the designs, mechanisms and applications of single-molecule FETs are summarized.

Nanoscale Patterning of Graphene Field-Effect Transistors for Single-Molecule Functionalization and Time Series

With the discovery of low-dimensional materials, the extreme miniaturization of field-effect transistors (FETs) has revealed such devices as powerful sensors for experiments at the single-molecule scale. In particular, FET devices functionalized with an individual molecule have been able to record, via fluctuations in the electrical conductance, various types of single-molecule dynamic changes, for example enzymatic activity1 DNA hybridization2,3 or DNA folding4. So far, such studies have mostly been carried out with FETs based on 1D materials such as carbon nanotubes (CNTs) or silicon nanowires (SiNWs). The 1D geometry of these materials facilitates the capture of a 0D molecule and provides enhanced sensitivity of the conductance to the functionalized site. However, FETs based on 1D materials often present scalability issues, due to challenges in controlling their growth and/or assembly.Here, we propose an approach based on nanoscale patterning of a 2D material to assemble FET arrays compatible for single-molecule capture and detection. First, we report wafer-scale microfabrication of arrays of graphene field-effect transistors (GFETs) with micron-scale channels. Like its 1D counterpart, graphene presents a high and sensitive electrical conductivity as well as carbon-based surface chemistry for single-molecule functionalization. GFET arrays were built from high-quality graphene synthesized by chemical vapor deposition (CVD) and transferred using a custom automated process on patterned electrodes. Then, we describe the nanoscale patterning of graphene channels in nanoconstrictions suitable for single-molecule functionalization and sensitivity. Using electron-beam lithography (EBL) and deep reactive ion etching (DRIE), we were able to produce a combination of high-resolution features in graphene (<100nm) as well as nanofluidics reactions chambers (<50nm), to promote single-molecule chemistry on the graphene. We will present our recent results in functionalizing these nanoconstrictions with single-stranded DNA and in collecting high-resolution electrical time series from these constructs. Finally, we will discuss the performance of such graphene-based devices for single-molecule experiments. Bibliography Choi, Y., Weiss, G. A. & Collins, P. G. Single molecule recordings of lysozyme activity. Physical Chemistry Chemical Physics (2013). doi:10.1039/c3cp51356d Sorgenfrei, S. & Shepard, K. L. Label-free field-effect-based single-molecule detection of DNA hybridization kinetics. Nat. Nanotechnol. 6, 126–132 (2011). Vernick, S. et al. Electrostatic melting in a single-molecule field-effect transistor with applications in genomic identification. Nat. Commun. 8, 1–9 (2017). Bouilly, D. et al. Single-molecule reaction chemistry in patterned nanowells. Nano Lett. 16, 4679–4685 (2016).

Lateral scaling and positioning effects of top-gate electrodes on single-molecule field-effect transistors

Molecular electronics aims at integrating controllable molecular devices into circuits or machines to realize certain functions. According to device configuration, molecular field-effect transistors with top-gate electrodes have great advantages for integration. Nevertheless, from technical aspects, it is difficult to control lateral scale and position of a top-gate electrode precisely. Therefore, one problem arises in how lateral scaling and positioning effects of a top-gate electrode affect device performance. To solve this problem, the electronic transport properties of single-molecule field-effect transistor configurations modulated by a series of partial-scale top-gate electrodes with different lateral scales and positions are studied by using non-equilibrium Green’s function in combination with density functional theory, and compared with those of the full gate electrode (can be considered as a bottom gate electrode). The results show that lateral scaling and positioning effects indeed have a great impact on electronic transport properties of single-molecule field-effect transistor configurations. For -saturated 1,12-dodecanedithiol devices, larger lateral scale of a partial-scale top-gate electrode obtains larger amplification coefficient (ratio of device conductances with/without a gate electrode), and even larger than that of the full gate electrode. While lateral positioning effect has little influence on this device. For -conjugated 1,3,5,7,9,11-dodehexaene-1,12-dithiol devices, performance of a partial-scale top-gate electrode mainly depends on locations of its two edges, i.e. the number of bonds that it breaks. These results will provide theoretical directions in device designing and manufacturing in the future.

Dirac-cone induced gating enhancement in single-molecule field-effect transistors.

Using graphene as electrodes provides an opportunity for fabricating stable single-molecule field-effect transistors (FETs) operating at room temperature. However, the role of the unique graphene band structure in charge transport of single-molecule devices is still not clear. Here we report the Dirac-cone induced electrostatic gating effects in single-molecule FETs with graphene electrodes and a solid-state local bottom gate. With the highest occupied molecular orbital (HOMO) as the dominating conduction channel and the graphene leads remaining intrinsic at zero gate voltage, electrostatic gating on the HOMO and the density of states of graphene at the negative gate polarity reinforces each other, resulting in an enhanced conductance modulation. In contrast, gating effects on the HOMO and the graphene states at the positive gate polarity are opposite. Depending on the gating efficiencies, the conductance can decrease, increase or remain almost unchanged when a more positive gate voltage is applied. Our observations can be well understood by a modified single-level model taking into account the linear dispersion of graphene near the Dirac point. Single-molecule FETs with Dirac-cone enhanced gating have shown high performances, with the modulation of a wide range of current over one order of magnitude. Our studies highlight the advantages of using graphene as an electrode material for molecular devices and pave the way for single-molecule FETs toward circuitry applications.

Electrostatic melting in a single-molecule field-effect transistor with applications in genomic identification

The study of biomolecular interactions at the single-molecule level holds great potential for both basic science and biotechnology applications. Single-molecule studies often rely on fluorescence-based reporting, with signal levels limited by photon emission from single optical reporters. The point-functionalized carbon nanotube transistor, known as the single-molecule field-effect transistor, is a bioelectronics alternative based on intrinsic molecular charge that offers significantly higher signal levels for detection. Such devices are effective for characterizing DNA hybridization kinetics and thermodynamics and enabling emerging applications in genomic identification. In this work, we show that hybridization kinetics can be directly controlled by electrostatic bias applied between the device and the surrounding electrolyte. We perform the first single-molecule experiments demonstrating the use of electrostatics to control molecular binding. Using bias as a proxy for temperature, we demonstrate the feasibility of detecting various concentrations of 20-nt target sequences from the Ebolavirus nucleoprotein gene in a constant-temperature environment.

Electrostatic Control of DNA Hydridization Kinetics Studied with the Single-Molecule Field-Effect Transistor

Electrostatic Control of DNA Hydridization Kinetics Studied with the Single-Molecule Field-Effect Transistor

Probing DNA Conformational Changes in Real Time Using Single-Molecule Electronic Sensors Based on Carbon Nanotube Field-Effect Transistors

In humans and other vertebrates, the ends of chromosomes are protected by a buffer region of single-stranded DNA (ssDNA) called the telomere. Telomeric ssDNA is made of multiple repeats of the nucleotide sequence GGGTTA and can form three-dimensional folded structures called G-quadruplexes, which are stabilized by monovalent cations like K+ or Na+. The formation of G-quadruplexes has been shown to disrupt the activity of enzymes necessary for telomere maintenance, enzymes that are also upregulated in many types of cancer cells and play a significant role in regulating cellular senescence. As such, G-quadruplexes are considered a potential therapeutic target for inhibiting the proliferation of cancerous cells and for treating aging-associated diseases. In this work, we use single-molecule field-effect transistors (smFETs) made from carbon nanotube devices to characterize the folding and unfolding dynamics of short stretches of telomeric ssDNA, and investigate the stability of G-quadruplex structures. First, we demonstrate a method for reliably functionalizing a carbon nanotube device with an individual ssDNA, using a combination of nano-confined covalent chemistry and bioconjugation reactions. The resulting smFET devices are then used to detect changes in the conformation of the ssDNA, in real-time and over a broad range of time scales. In the presence of K+ or Na+, we observe quantized fluctuations between high and low states in the conductance, which we are able to assign to the unfolded and G-quadruplex conformations, respectively. We discuss the effect of the identity and concentration of these two cations on the folding dynamics of G-quadruplex-forming ssDNA. In particular, we find that the folded G-quadruplex structure is 10 times more stable in K+ than Na+. This approach paves the way for investigations of the folding dynamics of various biomolecules at the single-molecule scale.

Complementary Metal-Oxide-Semiconductor Integrated Carbon Nanotube Arrays: Toward Wide-Bandwidth Single-Molecule Sensing Systems.

There is strong interest in realizing genomic molecular diagnostic platforms that are label-free, electronic, and single-molecule. One attractive transducer for such efforts is the single-molecule field-effect transistor (smFET), capable of detecting a single electronic charge and realized with a point-functionalized exposed-gate one-dimensional carbon nanotube field-effect device. In this work, smFETs are integrated directly onto a custom complementary metal-oxide-semiconductor chip, which results in an array of up to 6000 devices delivering a measurement bandwidth of 1 MHz. In a first exploitation of these high-bandwidth measurement capabilities, point functionalization through electrochemical oxidation of the devices is observed with microsecond temporal resolution, which reveals complex reaction pathways with resolvable scattering signatures. High-rate random telegraph noise is detected in certain oxidized devices, further illustrating the measurement capabilities of the platform.

Label-Free, High-Time-Resolution, Single-Molecule Studies of Riboswitch Folding

Riboswitches are genetic control elements that are located within the 5’ untranslated region of predominantly bacterial mRNAs and that undergo metabolite-dependent structural rearrangements that regulate mRNA transcription, splicing, translation, or stability in response to specific metabolites. A molecular-resolution understanding of the mechanisms through which riboswitches fold, specifically recognize and bind their target metabolites, and subsequently influence cellular processes is essential for development of next-generation antibiotics that target riboswitches and for engineering riboswitches for use in synthetic biology applications. Motivated by this, previous studies using single-molecule fluorescence and force spectroscopy methods have provided insights into the metabolite-responsive folding and function of several riboswitches. Despite the power of these methods, however, they suffer from intrinsic disadvantages (e.g., fluorophore labeling, invasive forces, etc.) that can corrupt and/or restrict the mechanistic information that they provide. Additionally, the resolution of these methods is generally limited to tens-to-hundreds of milliseconds, resulting in time-averaging of RNA dynamics that occur on faster timescales. To overcome these limitations, we have developed carbon nanotube-based, single-molecule field-effect transistors (smFETs) that enable label-free, high-time-resolution, single-molecule studies of RNA folding and dynamics. Using these novel smFET devices, we have investigated the dynamics of the pbuE adenine-responsive riboswitch at the single-molecule level and a time resolution of tens of microseconds. Our results show that the adenine-free riboswitch exists in a conformational equilibrium between at least four states, some of which exchange on timescales too fast to have been previously observed. Using a combination of adenine, adenine analogs, and riboswitch mutants, we have detected the formation of an initial, highly transient riboswitch-metabolite complex whose evolution to the final, stably bound complex we are currently investigating. Taken together with previous studies, our results are providing unprecedented insights into the structure, dynamics, and function of this paradigmatic metabolite-responsive riboswitch.

Label-Free, High-Time-Resolution, Single-Molecule Studies of Riboswitch Folding

Riboswitches are genetic control elements that are located within the 5’ untranslated region of predominantly bacterial mRNAs and that undergo metabolite-dependent structural rearrangements that regulate mRNA transcription, splicing, translation, or stability in response to specific metabolites. A molecular-resolution understanding of the mechanisms through which riboswitches fold, specifically recognize and bind their target metabolites, and subsequently influence cellular processes is essential for development of next-generation antibiotics that target riboswitches and for engineering riboswitches for use in synthetic biology applications. Motivated by this, previous studies using single-molecule fluorescence and force spectroscopy methods have provided insights into the metabolite-responsive folding and function of several riboswitches. Despite the power of these methods, however, they suffer from intrinsic disadvantages (e.g., fluorophore labeling, invasive forces, etc.) that can corrupt and/or restrict the mechanistic information that they provide. Additionally, the resolution of these methods is generally limited to tens-to-hundreds of milliseconds, resulting in time-averaging of RNA dynamics that occur on faster timescales. To overcome these limitations, we have developed carbon nanotube-based, single-molecule field-effect transistors (smFETs) that enable label-free, high-time-resolution, single-molecule studies of RNA folding and dynamics. Using these novel smFET devices, we have investigated the dynamics of the pbuE adenine-responsive riboswitch at the single-molecule level and a time resolution of tens of microseconds. Our results show that the adenine-free riboswitch exists in a conformational equilibrium between at least four states, some of which exchange on timescales too fast to have been previously observed. Using a combination of adenine, adenine analogs, and riboswitch mutants, we have detected the formation of an initial, highly transient riboswitch-metabolite complex whose evolution to the final, stably bound complex we are currently investigating. Taken together with previous studies, our results are providing unprecedented insights into the structure, dynamics, and function of this paradigmatic metabolite-responsive riboswitch.

Electrochemical Gating of Charge Transport in Single Macrocycle Molecular Switches

Molecular switches, i.e., molecular scale devices that can be turned on and off, are of long standing interest. In the quest for miniaturization of electronic devices, the development of electrical switches of molecular dimensions has been identified as an important target of practical importance. While much progress has been made in designing functional molecular scale electrical switches, i.e., molecular cores whose intrinsic conductivity can be externally modulated, the question of contact resistance has not been sufficiently addressed. Our novel strategy for the regulation of charge transport through single molecule junctions combines external stimuli using a variation of electrode potential in an electrochemical environment, internal modulation of molecular structures and optimization of anchoring groups. Our synthetic collaborators have designed redox-active benzodifuran (BDF) compounds as functional electronic units which we have used to fabricate metal-molecule-metal (m-M-m) junction devices by scanning tunneling microscopy (STM) and mechanically controllable break junctions (MCBJ).[1] The conductance of BDF terminated thiol, the standard anchoring group for molecular scale electronic components, can be tuned by changing the electrode potentials in an ionic liquid electrolyte to show a clear single molecule field effect transistor (FET) behavior. We hypothesized that we could optimize the response by appropriate choice of molecular anchoring group.[2] Guided by our earlier investigations, a BDF molecule tailored with carbodithioate (-CS2-) anchoring groups was synthesized. Our studies show that replacement of thiol by carbodithioate not only increases the junction conductance, but also substantially improves the FET response by enhancing the on/off ratio from 2.5 to 8. [1] Regulating a Benzodifuran Single Molecule Redox Switch via Electrochemical Gating and Optimization of Molecule/Electrode Coupling, Zhihai Li, Hui Li, Songjie Chen, Toni Froehlich, Christian Schönenberger, Michel Calame, Silvio Decurtins, Shi-Xia Liu and Eric Borguet, Journal of the American Chemical Society 136, 25 8867-8870 (2014). [2] Optimizing Single-Molecule Conductivity of Conjugated Organic Oligomers with Conjugated Carbodithioate Linkers, Yangjun Xing, Tae-Hong Park, Ravindra Venkatramani, Shahar Keinan, David N. Beratan, Michael J. Therien, and Eric Borguet, Journal of the American Chemical Society 132 (23), 7946-7956 (2010). Figure 1

Cross polarization effect of donor-acceptor group on a potential single-molecule transistor

Theoretical investigation of the polarization effect on a potential single-molecule transistor has been studied with density functional theory. 4,4′-(2-Amino-5-nitro-1,4-phenylene)bis(ethyne-2,1-diyl) dibenzenethiol (AN-OPE), containing a donor and an acceptor (D–A) crossed to its oligo(p-phenylene-ethynylene) (OPE) backbone, was used as a prototype for this study. Simulation results indicate that AN-OPE has a higher on/off ratio on conductance than OPE because of the larger polarization along the D–A direction. This high on/off ratio was proved by the 20 times variation in molecular charge, 15 times variation in bond lengths, 49 times variation in polarizability, 9 times variation in the rotation angles, and 13 times variation in the highest occupied molecular orbital–lowest unoccupied molecular orbital gaps under the same gate using B3LYP/6-31G (d, p). And results imply that conjugated molecules with a cross D–A structure could be a good direction for constructing a better single-molecule field-effect transistor. Copyright © 2014 John Wiley & Sons, Ltd.

Gating of single molecule transistors: Combining field-effect and chemical control

Previously we have demonstrated that several structural features are crucial for the functionality of molecular field-effect transistors. The effect of additional structural aspects of molecular wires is explored. These include the type of, the thiol binding location on, and the chemical substitutions of a conjugated system. Pentacene, porphyrin, and the Tour-Reed devices are utilized as model systems. The thiol binding location is shown to have a varied effect on the transmission of a system depending on the molecular orbitals involved. Substitution by electron withdrawing and donating groups is illustrated to have a substantial effect on the transmission of single molecule devices. The substitution effect is either a simple energy shifting effect or a more complicated resonance effect, and can be used to effectively tune the electronic behavior of a single molecule field effect transistor.

Single-molecule field-effect transistors: A computational study of the effects of contact geometry and gating-field orientation on conductance-switching properties

The relation of geometric features to the effect of gating electric fields on the conductance through conjugated systems is investigated by electronic transmission calculations employing Green's function based modeling. Switching is only induced if the field is applied in an orientation which results in energy shifting of the molecular orbitals. This is found to depend on the orientation of the field with respect to the plane defined by the molecular conjugation. The switching can be quenched by structural rearrangement of the chemical bonds to the bulk, where the relative position of the electrodes is modified.