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1. Multi-resolution simulation of DNA transport through large synthetic nanostructures

   https://doi.org/10.1039/d1cp04589j  

   Choudhary, Adnan; Maffeo, Christopher; Aksimentiev, Aleksei (February 2022, Physical Chemistry Chemical Physics)

   Modeling and simulation has become an invaluable partner in development of nanopore sensing systems. The key advantage of the nanopore sensing method – the ability to rapidly detect individual biomolecules as a transient reduction of the ionic current flowing through the nanopore – is also its key deficiency, as the current signal itself rarely provides direct information about the chemical structure of the biomolecule. Complementing experimental calibration of the nanopore sensor readout, coarse-grained and all-atom molecular dynamics simulations have been used extensively to characterize the nanopore translocation process and to connect the microscopic events taking place inside the nanopore to the experimentally measured ionic current blockades. Traditional coarse-grained simulations, however, lack the precision needed to predict ionic current blockades with atomic resolution whereas traditional all-atom simulations are limited by the length and time scales amenable to the method. Here, we describe a multi-resolution framework for modeling electric field-driven passage of DNA molecules and nanostructures through to-scale models of synthetic nanopore systems. We illustrate the method by simulating translocation of double-stranded DNA through a solid-state nanopore and a micron-scale slit, capture and translocation of single-stranded DNA in a double nanopore system, and modeling ionic current readout from a DNA origami nanostructure passage through a nanocapillary. We expect our multi-resolution simulation framework to aid development of the nanopore field by providing accurate, to-scale modeling capability to research laboratories that do not have access to leadership supercomputer facilities. 

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2. Osmotically Driven and Detected DNA Translocations

   https://doi.org/10.1038/s41598-019-51049-4  

   McMullen, Angus; Araujo, George; Winter, Michele; Stein, Derek (December 2019, Scientific Reports)

   Abstract A salinity gradient propels a DNA molecule through a solid-state nanopore and generates an ionic current whose change allows for the detection of the translocation. Measurements and theoretical analyses reveal the role of diffusio-osmosis in driving these phenomena: After accounting for known salinity-dependent electrode effects, the measured current change caused by the presence of a DNA molecule inside the nanopore and the DNA translocation speed through it both increase with the magnitude of the applied salinity gradients. The effects are consistent with the theory of diffuisio-osmosis and strong enough to enable DNA translocations to overcome an applied retarding potential of tens of millivolts. This work illustrates how salinity gradients can be used to power and operate a nanopore sensor. 

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3. Detecting DNA translocation through a nanopore using a van der Waals heterojunction diode

   https://doi.org/10.1073/pnas.2422135122  

   Chen, Sihan; Huang, Siyuan; Son, Jangyup; Han, Edmund; Watanabe, Kenji; Taniguchi, Takashi; Huang, Pinshane Y; King, William P; van_der_Zande, Arend M; Bashir, Rashid (May 2025, Proceedings of the National Academy of Sciences)

   A long-unrealized goal in solid-state nanopore sensing is to achieve out-of-plane electrical sensing and control of DNA during translocation, which is a prerequisite for base-by-base ratcheting that enables DNA sequencing in biological nanopores. Two-dimensional (2D) heterostructures, with their capability to construct out-of-plane electronics with atomic layer precision, are ideal yet unexplored candidates for use as electrical sensing membranes. Here, we demonstrate a nanopore architecture using a vertical 2D heterojunction diode consisting of p-type WSe₂on n-type MoS₂. This diode exhibits rectified interlayer tunneling currents modulated by ionic potential, while the heterojunction potential reciprocally rectifies ionic transport through the nanopore. We achieve concurrent detection of DNA translocation using both ionic and diode currents and demonstrate a 2.3-fold electrostatic slowing of average translocation speed. Encapsulation layers enhance chemical and mechanical stability and durability while preserving the spatial resolution of atomically sharp 2D heterointerface for sensing. These results establish a paradigm for out-of-plane electrical sensing of single biomolecules. 

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4. Inverted duplicate DNA sequences increase translocation rates through sequencing nanopores resulting in reduced base calling accuracy

   https://doi.org/10.1093/nar/gkaa206  

   Spealman, Pieter; Burrell, Jaden; Gresham, David (April 2020, Nucleic Acids Research)

   Abstract Inverted duplicated DNA sequences are a common feature of structural variants (SVs) and copy number variants (CNVs). Analysis of CNVs containing inverted duplicated DNA sequences using nanopore sequencing identified recurrent aberrant behavior characterized by low confidence, incorrect and missed base calls. Inverted duplicate DNA sequences in both yeast and human samples were observed to have systematic elevation in the electrical current detected at the nanopore, increased translocation rates and decreased sampling rates. The coincidence of inverted duplicated DNA sequences with dramatically reduced sequencing accuracy and an increased translocation rate suggests that secondary DNA structures may interfere with the dynamics of transit of the DNA through the nanopore. 

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5. Nonmonotonic polymer translocation kinetics through nanopores under changing surface–polymer interactions

   https://doi.org/10.1063/5.0189057  

   Manohar, Neha; Riggleman, Robert A; Lee, Daeyeon; Stebe, Kathleen J (February 2024, The Journal of Chemical Physics)

   Understanding the dynamics of polymers in confined environments is pivotal for diverse applications ranging from polymer upcycling to bioseparations. In this study, we develop an entropic barrier model using self-consistent field theory that considers the effect of attractive surface interactions, solvation, and confinement on polymer kinetics. In this model, we consider the translocation of a polymer from one cavity into a second cavity through a single-segment-width nanopore. We find that, for a polymer in a good solvent (i.e., excluded volume, u0 > 0), there is a nonmonotonic dependence of mean translocation time (τ) on surface interaction strength, ɛ. At low ɛ, excluded volume interactions lead to an energetic penalty and longer translocation times. As ɛ increases, the surface interactions counteract the energetic penalty imposed by excluded volume and the polymer translocates faster through the nanopore. However, as ɛ continues to increase, an adsorption transition occurs, which leads to significantly slower kinetics due to the penalty of desorption from the first cavity. The ɛ at which this adsorption transition occurs is a function of the excluded volume, with higher u0 leading to an adsorption transition at higher ɛ. Finally, we consider the effect of translocation across different size cavities. We find that the kinetics for translocation into a smaller cavity speeds up while translocation to a larger cavity slows down with increasing ɛ due to higher surface contact under stronger confinement. 

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