We discuss multiscale simulations of long biopolymer translocation through wide nanopores that can accommodate multiple polymer strands. The simulations provide clear evidence of folding quantization, namely, the translocation proceeds through multi-folded configurations characterized by a well-defined integer number of folds. As a consequence, the translocation time acquires a dependence on the average folding number, which results in a deviation from the single-exponent power-law characterizing single-file translocation through narrow pores. The mechanism of folding quantization allows polymers above a threshold length (approximately $1,000$ persistence lengths for double-stranded DNA) to exhibit cooperative behavior and as a result to translocate noticeably faster.
We present results from our simulations of biopolymer translocation in a solvent which explain the main experimental findings. The forced translocation can be described by simple force balance arguments for the relevant range of pore potentials in experiments and biological systems. Scaling of translocation time with polymer length varies with pore force and friction. Hydrodynamics affects this scaling and significantly reduces translocation times.
We present a detailed description of biopolymer translocation through a nanopore in the presence of a solvent, using an innovative multi-scale methodology which treats the biopolymer at the microscopic scale as combined with a self-consistent mesoscopic description for the solvent fluid dynamics. We report evidence for quantized current blockade depending on the folding configuration and offer detailed information on the role of hydrodynamic correlations in speeding-up the translocation process.
Numerical results on the translocation of long biopolymers through mid-sized and wide pores are presented. The simulations are based on a novel methodology which couples molecular motion to a mesoscopic fluid solvent. Thousands of events of long polymers (up to 8000 monomers) are monitored as they pass through nanopores. Comparison between the different pore sizes shows that wide pores can host a larger number of multiple biopolymer segments, as compared to smaller pores. The simulations provide clear evidence of folding quantization in the translocation process as the biopolymers undertake mu…
We employ a multiscale approach to model the translocation of biopolymers through nanometer size pores. Our computational scheme combines microscopic Langevin molecular dynamics (MD) with a mesoscopic lattice Boltzmann (LB) method for the solvent dynamics, explicitly taking into account the interactions of the molecule with the surrounding fluid. Both dynamical and statistical aspects of the translocation process were investigated, by simulating polymers of various initial configurations and lengths. For a representative molecule size, we explore the effects of important parameters that enter …
We investigate the process of biopolymer translocation through a narrow pore using a multiscale approach which explicitly accounts for the hydrodynamic interactions of the molecule with the surrounding solvent. The simulations confirm that the coupling of the correlated molecular motion to hydrodynamics results in significant acceleration of the translocation process. Based on these results, we construct a phenomenological model which incorporates the statistical and dynamical features of the translocation process and predicts a power law dependence of the translocation time on the polymer len…
We present a multiscale approach to the modeling of polymer dynamics in the presence of a fluid solvent. The approach combines Langevin Molecular Dynamics (MD) techniques with a mesoscopic Lattice-Boltzmann (LB) method for the solvent dynamics. A unique feature of the present approach is that hydrodynamic interactions between the solute macromolecule and the aqueous solvent are handled explicitly, and yet in a computationally tractable way due to the dual particle-field nature of the LB solver. The suitability of the present LB-MD multiscale approach is demonstrated for the problem of polymer …
Graphene nanopore based sensor devices are exhibiting the great potential for the detection of DNA. To understand the fundamental aspects of DNA translocating through a graphene nanopore, in this work, molecular dynamics (MD) simulations and potential of mean force (PMF) calculations were carried out to investigate the layer impact of small graphene nanopore (2 nm-3 nm) to DNA translocation. It was observed that the ionic conductance was sensitive to graphene layer of open-nanopores, the probability for DNA translocation through graphene nanopore was related with the thickness of graphene nano…
We revisit the one-dimensional stochastic model of Lubensky and Nelson [Biophys. J 77, 1824 (1999)] for the electrically driven translocation of polynucleotides through alpha-hemolysin pores. We show that the model correctly describes two further important properties of the experimentally observed translocation time distributions, namely their spread (width) and their exponential decay. The resulting overall agreement between theoretical and experimental translocation time distributions is thus very good.
The detection of biomolecules at the single molecular level have important applications in the fields of biosensing and biomedical diagnosis. Solid state nanopore (SS-nanopore) is an effective tool to perform the single molecular detection, due to its unique properties of label-free and less sample consumption. The current SS-nanopore translocations of small biomolecules are driven by the electronic field force, thus easily influenced by the charges, shapes and sizes of the target molecules. Therefore, it remains a great challenge to control biomolecules to translocate through SS-nanopore, par…
We employ a multiscale approach to model the translocation of biopolymers through nanometer size pores. Our computational scheme combines microscopic Molecular Dynamics (MD) with a mesoscopic Lattice Boltzmann (LB) method for the solvent dynamics, explicitly taking into account the interactions of the molecule with the surrounding fluid. We describe an efficient parallel implementation of the method which exhibits excellent scalability on the Blue Gene platform. We investigate both dynamical and statistical aspects of the translocation process by simulating polymers of various initial configur…
A multiscale approach is used to simulate the translocation of DNA through a nanopore. Within this scheme, the interactions of the molecule with the surrounding fluid (solvent) are explicitly taken into account. By generating polymers of various initial configurations and lengths we map the probability distibutions of the passage times of the DNA through the nanopore. A scaling law behavior for the most probable of these times with respect to length is derived, and shown to exhibit an exponent that is in a good agreement with the experimental findings. The essential features of the DNA dynamic…
Solid-state nanopores are single molecule sensors that measure changes in ionic current as charged polymers such as DNA pass through. Here, we present comprehensive experiments on the length, voltage and salt dependence of the frequency of double-stranded DNA translocations through conical quartz nanopores with mean opening diameter 15 nm. We observe an entropic barrier limited, length dependent translocation frequency at 4M LiCl salt concentration and a drift-dominated, length independent translocation frequency at 1M KCl salt concentration. These observations are described by a unifying conv…
We investigate the problem of polymer translocation through a nanopore in the absence of an external driving force. To this end, we use the two-dimensional (2D) fluctuating bond model with single-segment Monte Carlo moves. To overcome the entropic barrier without artificial restrictions, we consider a polymer which is initially placed in the middle of the pore, and study the escape time required for the polymer to completely exit the pore on either end. In particular, we examined the effect of the pore length on the escape time.
Chaperone-assisted translocation through a nanopore embedded in membrane holds a prominent role in the transport of biopolymers. Inspired by classical Brownian ratchet, we develop a theoretical framework characterizing such translocation process through a master equation approach. In this framework, the polymer chain, provided with reversible binding of chaperones, undergoes forward/backward diffusion, which is rectified by chaperones. We drop the assumption of timescale separation and keep the length of a polymer chain finite, both of which happen to be the key points in most of the previous …
DNA capture with high fidelity is an essential part of nanopore translocation. We report several important aspects of the capture process and subsequent translocation of a model DNA polymer through a solid-state nanopore in presence of an extended electric field using the Brownian dynamics simulation that enables us to record statistics of the conformations at every stage of the translocation process. By releasing the equilibrated DNAs from different equipotentials, we observe that the capture time distribution depends on the initial starting point and follows a Poisson process. The field grad…
Using Langevin dynamics simulations, we investigate the dynamics of polymer translocation into a circular nanocontainer through a nanopore under a driving force $F$. We observe that the translocation probability initially increases and then saturates with increasing $F$, independent of $ϕ$, which is the average density of the whole chain in the nanocontainer. The translocation time distribution undergoes a transition from a Gaussian distribution to an asymmetric distribution with increasing $ϕ$. Moreover, we find a nonuniversal scaling exponent of the translocation time as chain length, depend…
Chaperones are binding proteins which work as a driving force to bias the biopolymer translocation by binding to it near the pore and preventing its backsliding. Chaperones may have different spatial distribution. Recently we show the importance of their spatial distribution in translocation and how it effects on sequence dependency of the translocation time. Here we focus on homopolymers and exponential distribution. As a result of the exponential distribution of chaperones, energy dependency of the translocation time will changed and one see a minimum in translocation time versus effective e…
The translocation of a polymer through a pore in a membrane separating fluids of different viscosities is studied via several computational approaches. Starting with the polymer halfway, we find that as a viscosity difference across the pore is introduced, translocation will predominately occur towards one side of the membrane. These results suggest an intrinsic pumping mechanism for translocation across cell walls which could arise whenever the fluid across the membrane is inhomogeneous. Somewhat surprisingly, the sign of the preferred direction of translocation is found to be strongly depend…
Recent experiments of translocation of double stranded DNA through nanopores [M. Wanunu \textit{et al.} Nature Nanotech. {\bf 5}, 160 (2010)] reveal that the DNA capture rate can be significantly influenced by a salt gradient across the pore. We show that osmotic flow combined with electrophoretic effects can quantitatively explain the experimental data on the salt-gradient dependence of the capture rate.
We investigate the translocation of stiff polymers in the presence of binding particles through a nanopore by two-dimensional Langevin dynamics simulations. We find that the mean translocation time shows a minimum as a function of the binding energy $ε$ and the particle concentration $ϕ$, due to the interplay of the force from binding and the frictional force. Particularly, for the strong binding the translocation proceeds with a decreasing translocation velocity induced by a significant increase of the frictional force. In addition, both $ε$ and $ϕ$ have an notable impact on the distribution …
Nanopores -- nanosized holes that can transport ions and molecules -- are very promising devices for genomic screening, in particular DNA sequencing. Both solid-state and biological pores suffer from the drawback, however, that the channel constituting the pore is long, viz. 10-100 times the distance between two bases in a DNA molecule (0.5 nm for single-stranded DNA). Here, we demonstrate that it is possible to realize and use ultrathin nanopores fabricated in graphene monolayers for single-molecule DNA translocation. The pores are obtained by placing a graphene flake over a microsize hole in…
We investigate theoretically the translocation of structured RNA/DNA molecules through narrow pores which allow single but not double strands to pass. The unzipping of basepaired regions within the molecules presents significant kinetic barriers for the translocation process. We show that this circumstance may be exploited to determine the full basepairing pattern of polynucleotides, including RNA pseudoknots. The crucial requirement is that the translocation dynamics (i.e., the length of the translocated molecular segment) needs to be recorded as a function of time with a spatial resolution o…
Nanopore resistive pulse techniques are based on analysis of current or voltage spikes in the recorded signal. These spikes result from translocation of nanometer sized analytes through a nanopore. The most important information that needs to be extracted is the duration, amplitude and number of the translocation spikes. The recorded signal is usually considerably noisy, with a huge baseline drift and hundreds of translocation spikes. Thus, incorporation of suitable signal processing algorithms is necessary for correct and fast detection of all the translocation spikes and to accurately measur…
In this short note, a correction is made to the recently proposed solution [1] to a 1D biased diffusion model for linear DNA translocation and a new analysis will be given to the data in [1]. It was pointed out [2] by us recently that this 1D linear translocation model is equivalent to the one that was considered by Schrodinger [3] for the Enrenhaft-Millikan measurements [4,5] on electron charge. Here we apply Schrodinger's first-passage-time distribution formula to the data set in [1]. It is found that Schrodinger's formula can be used to describe the time distribution of DNA translocation in…
We study unbiased translocation of a flexible polymer chain through a membrane pore under the influence of active noise and steric exclusion using Langevin dynamics simulations. The active noise is incorporated by introducing nonchiral and chiral active particles on one or both sides of the membrane. Translocation of the polymer into either side of the pore is assisted by an effective pulling due to particle activity and is hindered by an effective pushing due to steric repulsions between the polymer and active particles. As a result of the competition between these effective forces, we find a…
The threading of a polymer chain through a small pore is a classic problem in polymer dynamics and underlies nanopore sensing technology. However important experimental aspects of the polymer motion in a solid-state nanopore, such as an accurate measurement of the velocity variation during translocation, have remained elusive. In this work we analysed the translocation through conical quartz nanopores of a 7 kbp DNA double-strand labelled with six markers equally spaced along its contour. These markers, constructed from DNA hairpins, give direct experimental access to the translocation dynamic…
We report translocation experiments on double-strand DNA through a silicon oxide nanopore. Samples containing DNA fragments with seven different lengths between 2000 to 96000 basepairs have been electrophoretically driven through a 10 nm pore. We find a power-law scaling of the translocation time versus length, with an exponent of 1.26 $\pm$ 0.07. This behavior is qualitatively different from the linear behavior observed in similar experiments performed with protein pores. We address the observed nonlinear scaling in a theoretical model that describes experiments where hydrodynamic drag on the…
Double-stranded DNA translocates through sufficiently large nanopores either in a linear, single-file fashion or in a folded hairpin conformation when captured somewhere along its length. We show that the folding state of DNA can be controlled by changing the electrolyte concentration, pH and PEG content of the measurement buffer. At 1 M LiCl or 0.35 M KCl in neutral pH, single-file translocations make up more than 90% of the total. We attribute the effect to the onset of electroosmotic flow from the pore at low ionic strength. Our hypothesis on the critical role of flows is supported by the p…
This study demonstrates that the nanopore terraces constructed on a multilayer graphene sheet could be employed to con-trol the conformation and transportation of an ssDNA for nanopore sequencing. As adsorbed on a terraced graphene na-nopore, the ssDNA has no in-plane swing nearby the nanopore, and can be locked on graphene terraces in a stretched con-formation. Under biasing, the accumulated ions near the nanopore promote the translocation of the locked ssDNA, and also disturb the balance between the driven force and resistance force acted on the nucleotide in pore. A critical force is found …
We consider elongated cylindrical particles, modeling e.g. DNA fragments or nano-rods, while translocating under the action of an externally applied voltage through a solid state nanopore. Particular emphasis is put on the concomitant potential energy landscape, encountered by the particle on its passage through the pore due to the complex interplay of various electrohydrodynamic effects beyond the realm of small Debye lengths. We find that the net potential energy difference across the membrane may be of opposite sign for short and long particles of equal diameters and charge densities (e.g. …
The effect of the microscopic structure of a pore on polymer translocation is studied using Langevin dynamics simulation, and the consequence of introducing patterned stickiness inside the pore is investigated. It is found that the translocation process is extremely sensitive to the detailed structure of such patterns with faster than exponential dependence of translocation times on the stickiness of the pore. The stochastic nature of the translocation process leads to discernable differences between how polymers with different sequences go through specifically patterned pores. This notion is …
The advent of solid state nanodevices allows for interrogating the physico-chemical properties of a polyelectrolyte chain by electrophoretically driving it through a nanopore. Salient dynamical aspects of the translocation process have been recently characterized by theoretical and computational studies of model polymer chains free from self-entanglement. However, sufficiently long equilibrated chains are necessarily knotted. The impact of such topological "defects" on the translocation process is largely unexplored, and is addressed in this study. By using Brownian dynamics simulations on a c…
A hydrodynamic model for determining the electrophoretic speed of a polyelectrolyte through a nanopore is presented. It is assumed that the speed is determined by a balance of electrical and viscous forces arising from within the pore and that classical continuum electrostatics and hydrodynamics may be considered applicable. An explicit formula for the translocation speed as a function of the pore geometry and other physical parameters is obtained and is shown to be consistent with experimental measurements on DNA translocation through nanopores in silicon membranes. Experiments also show a we…
We investigate the translocation of rods with different charge distributions using hybrid Langevin Dynamics and Lattice Boltzmann (LD-LB) simulations. Electrostatic interactions are added to the system using the $P^3M$ algorithm to model the electrohydrodynamic interactions (EHI). We first examine the free-solution electrophoretic properties of rods with various charge distributions. Our translocation simulation results suggest that the order parameter is asymmetric during the capture and escape processes despite the symmetric electric field lines, while the impacts of the charge distribution …
The translocation of double-stranded DNA through a solid-state nanopore may either decrease or increase the ionic current depending on the ionic concentration of the surrounding solution. Below a certain crossover ionic concentration, the current change inverts from a current blockade to current enhancement. In this paper, we show that the crossover concentration for bundled DNA nanostructures composed of multiple connected DNA double-helices is lower than that of double-stranded DNA. Our measurements suggest that counterion mobility in the vicinity of DNA is reduced depending on the three-dim…
We demonstrate simultaneous measurements of DNA translocation into glass nanopores using ionic current detection and fluorescent imaging. We verify the correspondence between the passage of a single DNA molecule through the nanopore and the accompanying characteristic ionic current blockage. By tracking the motion of individual DNA molecules in the nanocapillary perpendicular to the optical axis and using a model, we can extract an effective mobility constant for DNA in our geometry under high electric fields.
We present a numerical study of forced polymer translocation by using two separate pore models. Both of them have been extensively used in previous forced translocation studies. We show that variations in the pore model affect the forced translocation characteristics significantly in the biologically relevant pore force, i.e. driving force, range. Details of the model are shown to change even the obtained scaling relations, which is a strong indication of strongly out-of-equilibrium dynamics in the computational studies which have not yet succeeded in addressing the characteristics of the forc…
Methods for reducing and directly controlling the speed of DNA through a nanopore are needed to enhance sensing performance for direct strand sequencing and detection/mapping of sequence-specific features. We have created a method for reducing and controlling the speed of DNA that uses two independently controllable nanopores operated with an active control logic. The pores are positioned sufficiently close to permit co-capture of a single DNA by both pores. Once co-capture occurs, control logic turns on constant competing voltages at the pores leading to a `tug-of-war' whereby the molecule is…
Single-molecule based 3rd generation DNA sequencing technologies have been explored with tremendous effort, among which nanopore sequencing is considered as one of the most promising to achieve the goal of $1,000 genome project towards personalized medicine. Solid state nanopore is consented to be complementary to protein nanopore and subjected to extensive investigations in the past decade. However, the prevailing solid-state nanopore preparation still relies on focused ion or electron beams, which are expensive and time consuming. Here we demonstrate the fabrication of nanopores down to 19 n…
We employ a three-dimensional molecular dynamics to simulate translocation of a polymer through a nanopore driven by an external force. The translocation is investigated for different three pore diameter and two different external forces. In order to see the polymer and pore interaction effects on translocation time, we studied 9 different interaction energies. Moreover, to better understand the simulation results we investigate polymer center of mass, shape factor and the monomer distribution through the translocation. Our results unveil that while increasing the polymer-pore interaction ener…
Solid-state nanopores are promising tools for single molecule detection of both DNA and proteins. In this study, we investigate the patterns of ionic current blockades as DNA translocates into or out of the geometric confinement of such conically shaped pores. We studied how the geometry of a nanopore affects the detected ionic current signal of a translocating DNA molecule over a wide range of salt concentration. The blockade level in the ionic current depends on the translocation direction at a high salt concentration, and at lower salt concentrations we find a non-intuitive ionic current de…
The capture and translocation of biomolecules through nanometer-scale pores are processes with a potential large number of applications, and hence they have been intensively studied in the recent years. The aim of this paper is to review existing models of the capture process by a nanopore, together with some recent experimental data of short single- and double-stranded DNA captured by Cytolysin A (ClyA) nanopore. ClyA is a transmembrane protein of bacterial origin which has been recently engineered through site-specific mutations, to allow the translocation of double- and single-stranded DNA.…
The passage of DNA through a nanopore can be effectively decomposed into two distinct phases, docking and actual translocation. In experiments each phase is characterized by a distinct current signature which allows the discrimination of the two events. However, at low voltages a clear distinction of the two phases is lost. By using numerical simulations we clarify how the current signature associated to the docking events depends on the applied voltage. The simulations show that at small voltage the DNA globule enhances the pore conductance due to an enrichment of charge carriers. At high vol…
The translocation of a short DNA fragment through a nanopore is addressed when the perforated membrane contains an embedded electrode. Accurate numerical solutions of the coupled Poisson, Nernst-Planck, and Stokes equations for a realistic, fully three-dimensional setup as well as analytical approximations for a simplified model are worked out. By applying a suitable voltage to the membrane electrode, the DNA can be forced to preferably traverse the pore either along the pore axis or at a small but finite distance from the pore wall.
We present a new concept for the separation of DNA molecules by contour length that combines a nanofluidic ratchet, nanopore translocation and pulsed fields. Using Langevin Dynamics simulations, we show that it is possible to design pulsed field sequences to ratchet captured semiflexible molecules in such a way that only short chains successfully translocate, effectively transforming the nanopore process into a low pass molecular filter. We also show that asymmetric pulses can significantly enhance the device efficiency. The process itself can be performed with many pores in parallel, and it s…
In this work we study the assisted translocation of a polymer across a membrane nanopore, inside which a molecular motor exerts a force fuelled by the hydrolysis of ATP molecules. In our model the motor switches to its active state for a fixed amount of time, while it waits for an ATP molecule binding and triggering the impulse, during an exponentially distributed time lapse. The polymer is modelled as a beads-springs chain with both excluded volume and bending contributions, and moves in a stochastic three dimensional environment modelled with a Langevin dynamics at fixed temperature. The res…
We describe a recent multiscale approach based on the concurrent coupling of constrained molecular dynamics for long biomolecules with a mesoscopic lattice Boltzmann treatment of solvent hydrodynamics. The multiscale approach is based on a simple scheme of exchange of space-time information between the atomistic and mesoscopic scales and is capable of describing self-consistent hydrodynamic effects on molecular motion at a computational cost which scales linearly with both solute size and solvent volume. For an application of our multiscale method, we consider the much studied problem of biopo…
Chaperone-assisted biopolymer translocation is the main model proposed for translocation \textit{in vivo}. A dynamical Monte Carlo method is used to simulate the translocation of a stiff homopolymer through a nanopore driven by chaperones. Chaperones are proteins that bind to the polymer near the wall and prevent its backsliding through Cis side. The important parameters include binding energy, size and the local concentration of the chaperones. The profile of these local concentrations, build up the chaperones distribution. Here we investigate the effects of binding energy, size and the expon…
Using Langevin dynamics simulations, we investigate the dynamics of a flexible polymer translocation into a confined area under a driving force through a nanopore. We choose an ellipsoidal shape for the confinement and consider the dependence of the asymmetry of the ellipsoid measured by the aspect ratio on the translocation time. Compared with an isotropic confinement (sphere), an anisotropic confinement (ellipsoid) with the same volume slows down the translocation, and the translocation time increases with increasing the aspect ratio of the ellipsoid. We further find that it takes different …
During polymer translocation driven by e.g. voltage drop across a nanopore, the segments in the cis-side is incessantly pulled into the pore, which are then pushed out of it into the trans-side. This pulling and pushing polymer segments are described in the continuum level by nonlinear transport processes known, respectively, as fast and slow diffusions. By matching solutions of both sides through the mass conservation across the pore, we provide a physical basis for the cis and trans dynamical asymmetry, a feature repeatedly reported in recent numerical simulations. We then predict how the to…
High-fidelity analysis of translocating biomolecules through nanopores demands shortening the nanocapillary length to a minimal value. Existing nanopores and capillaries, however, inherit a finite length from the parent membranes. Here, we form nanocapillaries of zero depth by dissolving two superimposed and crossing metallic nanorods, thereby opening two overlapping nanofluidic channels molded in a polymeric resin. In an electrolyte, the interface shared by the crossing fluidic channels is mathematically of zero thickness and defines the narrowest constriction in the stream of ions through th…
Analyte translocation involves three phases: (i) diffusion in the loading solution; (ii) capture by the pore; (iii) threading. The capture process remains poorly characterized because it cannot easily be visualized or inferred from indirect measurements. The capture performance of a device is often described by a \textit{capture radius} generally defined as the radial distance $R^*$ at which diffusion-dominated dynamics cross over to field-induced drift. However, this definition is rather ambiguous and the related models are usually over-simplified and studied in the steady-state limit. We inv…
