Conceptually, extending the premise of bioelectronic interfaces down to the scale of single molecules is a straightforward goal. In practice, the challenges are purely technological. Single-molecule bioelectronic devices would have to involve features much smaller than state-of-the-art semiconductor electronics, and successful design would have unique requirements for sensitivity and stability.

These imposing specifications are balanced by the potential of enormous rewards, because single-molecule bioelectronics would be a breakthrough technology for biochemical research and applications. By peering past the ensemble behaviors of traditional characterization, single-molecule techniques aim to directly observe the stochastic fluctuations, instantaneous dynamics, and non-equilibrium behaviors that make up a molecule’s full functionality. Moreover, single-molecule measurements can uncover the unusual reaction trajectories of a genetically mutated protein or a receptor interacting with pharmacological inhibitors. Building a better understanding of the precise roles of proteins in complex biological processes is a grand challenge for biology, biochemistry, and biophysics in the twenty-first century.

These potential benefits have spurred the development of a variety of single-molecule techniques. Single-molecule fluorescence, specifically Förster resonance energy transfer (FRET), has become a standard tool for single-molecule biochemistry [1]. Meanwhile, single-molecule bioelectronics has remained elusive, despite the wide-ranging capabilities of modern solid state electronics.