Solid-state nanopores allow high-throughput single-molecule detection but identifying and even registering all translocating small molecules remain key challenges due to their high translocation speeds. We show here the same electric field that drives the molecules into the pore can be redirected to selectively pin and delay their transport. A thin high-permittivity dielectric coating on bullet-shaped polymer nanopores permits electric field leakage at the pore tip to produce a voltage-dependent surface field on the entry side that can reversibly edge-pin molecules. This mechanism renders molecular entry an activated process with sensitive exponential dependence on the bias voltage and molecular rigidity. This sensitivity allows us to selectively prolong the translocation time of short single-stranded DNA molecules by up to 5 orders of magnitude, to as long as minutes, allowing discrimination against their double-stranded duplexes with 97% confidence.

The presence of a small number (∼1000) of charged nanoparticles or macromolecules on the surface of an oppositely charged perm-selective membrane is shown to sensitively gate the ionic current through the membrane at a particular voltage, thus producing a voltage signal much larger than thermal noise. We show that, at sufficiently high voltages, surface vortices appear on the membrane surface and sustain an ion-depleted boundary layer that controls the diffusion length and ion current. An asymmetric vortex bifurcation occurs beyond a critical voltage to reduce the diffusion length and the differential resistance by half. Surface nanoparticles and molecules only affect this transition voltage in the membrane I–V curve. It is shown to shift by 2 ln10 (RT/F) ∼ 0.12 V for every decade increase in bulk target concentration, independent of sensor dimension and target/probe pair. Such universal features of the surface charge-sensitive nonlinear and nonequilibrium conductance allow us to develop very robust (a 2–3 decade dynamic range for highly heterogeneous samples with built-in control) yet sensitive (subpicomolar) and selective biosensors for highly charged molecules like nucleic acids and endotoxinsand for proteins with charged nanoparticle reporters.

We report the first analytical theory on the amplitude of resistive signals during molecular translocation through charged solid-state nanopores with variable cross-sectional area and piecewise-constant surface charge densities. By providing closed-form explicit algebraic expressions for the concentration profiles inside charged nanopores, this theory allows the prediction of baseline and translocation resistive signals without the need for numerical simulation of the electrokinetic phenomena. A transversely homogenized theory and an asymptotic expansion for weakly charged pores capture DC or quasi-static rectification due to field-induced intrapore concentration polarization (as a result of pore charge inhomogeneity or a translocating molecule). This theory, validated by simulations and experiments, is then used to explain why the amplitude of a single stranded DNA molecule can be twice as high as the amplitude of its double stranded counterpart. It also suggests designs for intrapore concentration polarization and volume exclusion effects that can produce biphasic and other amplitude fingerprints for high-throughput and yet discriminating molecular identification.

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We verify both theoretically and by simulation that an AC electric field, with a frequency much higher than the dissociation rate, can significantly accelerate the dissociation rate of biological molecules under isothermal conditions. The cumulative effect of the AC field is shown to break a key bottleneck by reducing the entropy (and increasing the free energy of the local minimum) via the alignment of the molecular dipole with the field. For frequencies below a resonant frequency which corresponds to the inverse Debye dipole relaxation time, the dissociation rate can be accelerated by a factor that scales as , where is the field frequency, is the field amplitude, and'() is the frequency-dependent real permittivity of the molecule. At large amplitudes, we find that the accelerated melting rate becomes universal, independent of duplex size and sequence, which is in drastic contrast to Ohmic thermal melting. We confirm our theory with isothermal all-atomic molecular dynamics simulation of short DNA duplexes with known melting rates, demonstrating several orders in enhancement with realistic fields.