A reflection on ‘Dipole effects on the formation of molecular junctions’

Abstract

The 2016 study ‘Dipole effects on the formation of molecular junctions’ (S. Tanimoto, M. Tsutsui, K. Yokota and M. Taniguchi, Nanoscale Horiz., 2016, 1, 399–406, https://doi.org/10.1039/C6NH00088F) demonstrated that strong electric fields can align molecular dipoles, stabilizing conformations and improving the reproducibility of tunnelling current measurements. The insight has since driven advances in low-noise electrode design, molecular orientation control, and active trapping strategies, enabling robust single-molecule detection in solution. This article highlights how electrostatic control has shaped the evolution of tunnelling-based biosensing and brought label-free, single-molecule sequencing closer to reality.

Background

Fast, low-cost genome analysis is anticipated to drive the next revolution toward precision medicine. Quantum tunnelling current measurements have long been regarded as a promising strategy for label-free identification of individual molecules, owing to their exceptional sensitivity to molecular electronic structure, a property particularly attractive for DNA and protein sequencing.^1,2 In this approach, a bias voltage is applied across a single digit nanometer electrode gap, allowing electrons to tunnel through a molecule transiently residing within the junction. While the resulting current trace serves as a unique electronic fingerprint for single-molecule identification,^3–6 realizing this method under aqueous, physiologically relevant conditions remains challenging. Stochastic fluctuations in molecular conformation cause significant variability in tunnelling conductance, while rapid molecular diffusion yields only brief and infrequent junction occupancy. These factors together have constrained the robustness, reproducibility, and throughput of tunnelling-based biosensing and sequencing in biological environments.

Dipole–field interactions for robust molecular junctions

Under the circumstances, the work ‘Dipole effects on the formation of molecular junctions’ published on 2016 introduced a novel approach to constrain molecular conformations within a nanoscale gap (https://doi.org/10.1039/C6NH00088F).⁷ Using a nanofabricated mechanically controllable break junction (MCBJ),⁸ electron tunnelling transport through different isomers of benzenediamine (BDA) was investigated in aqueous environments. It was discovered that the intense electric field (∼10⁸ V m⁻¹) generated across a ∼1 nm gap between gold electrodes, interacts with the intramolecular dipole moments to effectively lock their orientation. For the 1,2-benzenediamine isomer (o-BDA), which possesses a substantial permanent dipole, this field-induced alignment dramatically reduced conductance variability by stabilizing a specific molecular configuration. The result was a reproducible and well-defined tunnelling pathway, as evidenced by highly consistent conductance signatures. In contrast, the 1,3- and 1,4-benzenediamine isomers (m- and p-BDA), which exhibit smaller dipole moments, undergo no such alignment, resulting in significantly broader conductance distributions. The study provided the first experimental demonstration that strong local electric fields can suppress conformational fluctuations by aligning molecular dipoles, enabling the formation of more stable and uniform single-molecule junctions.

This insight revealed a compelling strategy: harnessing electrostatic forces—particularly dipole alignment—to enhance the reproducibility and stability of single-molecule tunnelling current measurements in solution. In principle, any analyte bearing a permanent or field-induced dipole moment could be favorably oriented upon entering the electrode gap, thereby increasing the likelihood of adopting a detectable configuration rather than undergoing stochastic reorientation or diffusing out of the junction. The 2016 study established a foundational physical principle for overcoming a major limitation of tunnelling-based sensing: the extreme sensitivity of tunnelling current to sub-angstrom displacements, where slight variations in molecular conformation can lead to conductance fluctuations spanning several orders of magnitude.⁹ By coupling molecular dipoles to an externally applied electric field, the approach suppresses conformational noise, stabilizing the conductance signature and thereby enhancing signal fidelity and molecular discriminability. This concept marks a critical advance toward making tunnelling-based sensors viable for high-precision applications such as DNA and protein sequencing (Fig. 1).

Fig. 1 Dipole alignment via the strong electric field between nanometer-spaced electrodes.

Technological progress enabled by dipole-controlled junctions

Since 2016, the concept of dipole-controlled junction formation has spurred a series of innovations aimed at stabilizing tunnelling gaps, suppressing noise, and directing molecular translocation, each reinforcing the fundamental idea that molecular control is essential for reliable single-molecule detection. Building on the insight that dipole–field interactions can be exploited to orient molecules within nanoscale gaps, subsequent efforts have significantly broadened the functional scope of tunnelling-based sensors. In the following, we highlight several key advances that stem directly from this principle, collectively marking critical progress toward the realization of robust single-molecule sensing via quantum tunnelling (Fig. 2).

Fig. 2 Advanced tunnelling current detectors for single-molecule analysis. (a) Insulator-shielded nanoelectrodes enable low-noise, high-speed tunnelling current measurements in aqueous environments by minimizing capacitive and ionic interference. (b) Atomically doped carbon nanotube (CNT) electrodes generate localized in-gap dipole fields that facilitate nucleotide trapping and orientation control within the tunnelling junction. (c) Alternating-current (AC) mode tunnelling sequencing using N-terminated CNT electrodes without capping structures, enhancing base-specific electronic contrast. (d) Dielectrophoretic trapping amplifies molecular capture efficiency, enabling single-molecule tunnelling current detection even at ultra-low analyte concentrations.

A key challenge in translating dipole-aligned tunnelling measurements to biosensing applications was the inherently high electrical noise in aqueous environments. Thermal fluctuations, surface charge dynamics at the electrode–solution interface, and ionic conduction, collectively generate a noisy background that can obscure the subtle current modulations associated with individual molecules. In 2017, two independent studies addressed this issue by introducing dielectric coatings on the nanoelectrodes.^10,11 These insulator-protected electrodes effectively suppressed the electric double-layer capacitance, a dominant high-frequency noise source in liquid-phase measurements. For example, a 25 nm SiO₂ coating on gold electrodes reduced the RMS current noise from ∼28 pA to ∼14 pA under a 0.5 V bias across a 2 nm gap, with thicker coatings achieving further suppression down to ∼7–9 pA approaching the intrinsic electronic noise floor of the measurement system. Beyond noise reduction, the decreased capacitance also enhanced the temporal resolution of the tunnelling signals by reducing the RC time constant, enabling faster sampling rates (up to 50 kHz). This improvement allowed detection of sharper and shorter-lived current spikes from single nucleotides that were previously masked by noise or temporally smeared by circuit response limitations. These advances suggested the critical role of junction noise engineering, alongside molecular orientation control, in capturing transient biomolecular dynamics and enhancing the discriminability of nucleic acid analytes (Fig. 2a).

Another promising direction has been the chemical functionalization or heteroatom doping of electrodes to exert greater control over molecular behavior within the junction. Building on the concept that external electric fields can align molecules, a natural question arises: can similar electrostatic effects be embedded directly into the electrode architecture? An example was reported by Jung et al. in 2018, who investigated nitrogen-doped carbon nanotube (CNT) electrodes for single-nucleotide detection.¹² Atomistic simulations revealed that substituting even a single nitrogen atom into the sp² carbon lattice at the CNT tip induces a localized dipole due to the higher electronegativity of nitrogen. As single-stranded DNA translocates through the CNT nanogap, these dopant sites can form transient hydrogen bonds with nucleobases, simultaneously slowing down their motion and biasing them toward an edge-on orientation, rather than a random face-on configuration. In effect, the nitrogen dopant acts as a built-in electrostatic anchor, functionally analogous to an external field for dipole-alignment.⁷

Jung et al. further showed that N-doping could increase the nucleotide residence time in the gap by up to ∼300%, enhancing both the stability and selectivity of base-specific interactions. This not only improved molecular discrimination but also suggested a route toward active modulation of DNA motion. They proposed incorporating the one-dimensional CNT gap into a two-dimensional nanopore membrane, such as a buckypaper platform, to leverage the advantages of solid-state nanopores for controlled electrophoretic transport, while enabling transverse tunnelling readout for base identification via their electronic structure. This work exemplifies a clear conceptual evolution for realizing a solid-state single-molecule sequencing platform, from recognizing the utility of dipole fields for molecular alignment, to the rational design of localized surface dipoles via heteroatom doping to reproducibly orient, stabilize, and slow, single-molecule translocation events (Fig. 2b).

An additional conceptual leap inspired by efforts to control molecular conformation is the use of alternating bias for molecular detection. In 2020, Djurišić et al. proposed a novel approach in which a nanopore device incorporating side-embedded, nitrogen-terminated CNT electrodes could distinguish single DNA bases, not by their absolute tunnelling current levels, but by the rectification characteristics of an AC-driven current signal.¹³ Functional groups at the electrode tips establish localized dipole fields at the electrode–solution interface, effectively generating an in-gap gating field. When a nucleotide enters the nanogap, this field, together with an applied alternating voltage, produces an asymmetric response in current flow between positive and negative bias polarities. Notably, each nucleotide yielded a distinct rectification ratio, providing a reliable basis for discrimination. Importantly, this rectifying behavior was predicted to be robust against variations in molecular orientation or position, a long-standing challenge in DC tunnelling detection. Because the rectification signal arises from field-induced shifting of molecular orbital levels relative to the electrode Fermi levels, small fluctuations in molecular geometry have limited impact. In effect, the dipole-generated field stabilizes the electronic alignment and acts as an orienting force. Theoretical modelling showed that dipole fields on the order of 1 eV nm⁻¹, attainable with N-terminated CNTs, can significantly modulate frontier orbital energies, giving rise to pronounced diode-like behavior. Although still theoretical at the time of publication, this AC rectification-based approach offers a compelling alternative to traditional DC tunnelling strategies, with the potential to circumvent critical limitations such as stochastic molecular reorientation and signal instability (Fig. 2c).

Perhaps the most direct embodiment of the conformation-pinning principle is the integration of tunnelling sensors with dielectrophoretic (DEP) trapping, enabling the active capture and positioning of molecules within the junction. A longstanding limitation in early tunnelling experiments was their reliance on passive diffusion for molecular entry into the nanoscale gap, resulting in sporadic detection events, especially at low analyte concentrations. In 2021, Tang et al. addressed this challenge by introducing a tunnelling nanoprobe that combines a high-frequency AC field for DEP with a double-nanopore electrode structure.¹⁴ The device utilizes a pair of carbon-coated electrodes embedded in a glass nanopipette. When an AC voltage is applied between the electrodes, a non-uniform electric field is generated at the tip, producing a dielectrophoretic force that actively pulls nearby molecules into the junction region. This active trapping mechanism dramatically enhances the molecular capture rate. Upon switching off the AC field and applying a DC bias, the captured molecule can be interrogated via tunnelling current measurements, enabling single-molecule detection at analyte concentrations as low as sub-femtomolar levels. The approach overcomes a fundamental bottleneck in tunnelling sensor technology by effectively resolving the low-throughput limitation through active molecular guidance. Moreover, the use of a self-contained nanopipette design eliminates the need for a solid-state substrate, affording the flexibility to bring the electrode gap into contact with soft or complex environments. The convergence of tunnelling detection with DEP-based molecular manipulation marks a significant advance, translating the principle of molecular orientation control into a versatile and high-throughput platform for single-molecule sensing (Fig. 2d).

Toward single-molecule sequencing: outlook and impact

The advancements since the 2016 study vividly illustrate how a foundational physical insight can catalyze sustained technological progress. By demonstrating that molecular orientation and conformation can be actively controlled within a nanoscale electronic junction, the original work laid key conceptual advance for addressing two of the most persistent challenges in single-molecule biosensing: accuracy and throughput. Subsequent innovations, ranging from junction noise suppression and electrode surface functionalization to novel electronic readout strategies and active molecular trapping, have each tackled different facets of these challenges. Together, they have propelled the field steadily toward the ambitious goal of sequencing DNA, RNA, and proteins one molecule at a time using quantum tunnelling.

The most compelling prospect may lie in the convergence of these diverse innovations into a unified sensing platform. The broader field of biosensing is increasingly intersecting with molecular electronics, driven by the shared goal of manipulating and interrogating individual molecules within electrode gaps. The conceptual shift introduced in 2016, that a molecular configuration in a tunnelling junction is not merely a matter of chance but can be guided and stabilized by electric fields, has become a foundational principle in this convergence. Whether through engineered dipole–field interactions, heteroatom doping, dielectrophoretic trapping, or alternating-bias readouts, researchers are now actively shaping the molecular environment to extract meaningful signals at the single-molecule level.

In retrospect, the study ‘Dipole effects on the formation of molecular junctions’⁷ demonstrated that even at the atomic scale, one can design the local electrostatic landscape to influence molecular behavior with remarkable specificity. This realization has had far-reaching implications—from stabilizing electronic junctions in aqueous media and minimizing signal noise, to developing field-responsive interfaces for high-throughput detection and chemically selective molecular recognition. It has ultimately enabled the ability to trap and analyze single biomolecules at biologically relevant concentrations, once thought unattainable. What once seemed an aspirational vision, real-time, direct, label-free sequencing of biopolymers via quantum tunnelling, is now within sight. The path forward is still under construction, but with a robust conceptual foundation and a growing suite of engineering tools, the horizon for single-molecule sequencing by quantum tunnelling has never looked closer.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 25K01639.

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