A Low-Noise Solid-State Nanopore Platform Based on a Highly Insulating Substrate

Abstract

A solid-state nanopore platform with a low noise level and sufficient sensitivity to discriminate single-strand DNA (ssDNA) homopolymers of poly-A40 and poly-T40 using ionic current blockade sensing is proposed and demonstrated. The key features of this platform are (a) highly insulating dielectric substrates that are used to mitigate the effect of parasitic capacitance elements, which decrease the ionic current RMS noise level to sub-10 pA and (b) ultra-thin silicon nitride membranes with a physical thickness of 5 nm (an effective thickness of 2.4 nm estimated from the ionic current) are used to maximize the signal-to-noise ratio and the spatial depth resolution. The utilization of an ultra-thin membrane and a nanopore diameter as small as 1.5 nm allow the successful discrimination of 40 nucleotide ssDNA poly-A40 and poly-T40. Overall, we demonstrate that this platform overcomes several critical limitations of solid-state nanopores and opens the door to a wide range of applications in single-molecule-based detection and analysis.

Graphene nanodevices for DNA sequencing

“…It may be possible to suppress this noise by reducing the area of the freestanding graphene [31], or by the use of multilayered structures [36,42,43]. Glass-based substrates may furthermore represent a good improvement, as low dielectric materials reduce the capacitive noise [44].…”

Probing the Small‐Molecule Inhibition of an Anticancer Therapeutic Protein‐Protein Interaction Using a Solid‐State Nanopore

“…[17,18] However,t he problem of excess noise,which corresponds to afew tens of pA to 100 pA, [19,20] remains to be resolved. [17,18] However,t he problem of excess noise,which corresponds to afew tens of pA to 100 pA, [19,20] remains to be resolved.…”

“…[20] Blocking the interaction between mouse double minute 2 (MDM2) and p53 transactivation domain (p53TAD) has been an attractive strategy for cancer therapy because it can restore p53 function, resulting in cancer cell apoptosis.U sing this therapeutic strategy,many p53TAD-mimetic lead compounds have been identified for cancer treatment. [20] Thestructure of the N-terminal p53TADbinding domain of MDM2 (PDB code:1 YCR) [23] showed dimensions of 3.1 nm 3.5 nm 4.2 nm, (Figure 1a). [21,22] Nutlin-3 structurally mimics the 15-residue a-helical p53TAD peptide (residues Ser15-Asn29) that binds to MDM2.…”

“…[1,2] Because drug development for enzyme targets has been limited by the difficulties in achieving sufficient specificity,P PI inhibitors with extremely high specificity have recently attracted considerable attention. [20] Blocking the interaction between mouse double minute 2 (MDM2) and p53 transactivation domain (p53TAD) has been an attractive strategy for cancer therapy because it can restore p53 function, resulting in cancer cell apoptosis.U sing this therapeutic strategy,many p53TAD-mimetic lead compounds have been identified for cancer treatment. Nanopore sensors have several unique advantages compared with more conventional techniques,including single-molecule resolution and ultrasensitivity,label-free and real-time measurements,a nd high-throughput detection.…”

DNA sequence-dependent ionic currents in ultra-small solid-state nanopores

“…The recognition capability of biological nanopores has been extended to enable detection of epigenetic modifications 16–18 , DNA damage 19,20 and RNA sequences 21 . Improvements in nanopore fabrication technology 22–24 , reduction of noise 25–29 , and the use of two-dimensional materials 30–34 have made DNA sequencing with solid-state nanopores feasible, and considerably expanded the repertoire of physical measurements that could be used for DNA sequence recognition 35–42 .…”