Conceptually, extending the premise of bioelectronic interfaces down to thescale of single molecules is a straightforward goal. In practice, thechallenges are purely technological. Single-molecule bioelectronic deviceswould have to involve features much smaller than state-of-the-artsemiconductor electronics, and successful design would have uniquerequirements for sensitivity and stability.

These imposing specifications are balanced by the potential of enormousrewards, because single-molecule bioelectronics would be a breakthroughtechnology for biochemical research and applications. By peering past theensemble behaviors of traditional characterization, single-moleculetechniques aim to directly observe the stochastic fluctuations,instantaneous dynamics, and non-equilibrium behaviors that make up amolecule’s full functionality. Moreover, single-molecule measurementscan uncover the unusual reaction trajectories of a genetically mutatedprotein or a receptor interacting with pharmacological inhibitors. Buildinga better understanding of the precise roles of proteins in complexbiological processes is a grand challenge for biology, biochemistry, andbiophysics in the twenty-first century.

These potential benefits have spurred the development of a variety ofsingle-molecule techniques. Single-molecule fluorescence, specificallyFörster resonance energy transfer (FRET), has become a standard tool forsingle-molecule biochemistry [1]. Meanwhile, single-molecule bioelectronicshas remained elusive, despite the wide-ranging capabilities of modern solidstate electronics.