Aleksei Aksimentiev

University of Illinois, Urbana-Champaign, Urbana, Illinois, United States

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Publications (92)500.5 Total impact

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    ABSTRACT: The DNA origami technique can enable functionalization of inorganic structures for single-molecule electric current recordings. Experiments have shown that several layers of DNA molecules, a DNA origami plate, placed on top of a solid-state nanopore is permeable to ions. Here, we report a comprehensive characterization of the ionic conductivity of DNA origami plates by means of all-atom molecular dynamics (MD) simulations and nanocapillary electric current recordings. Using the MD method, we characterize the ionic conductivity of several origami constructs, revealing the local distribution of ions, the distribution of the electrostatic potential and contribution of different molecular species to the current. The simulations determine the dependence of the ionic conductivity on the applied voltage, the number of DNA layers, the nucleotide content and the lattice type of the plates. We demonstrate that increasing the concentration of Mg(2+) ions makes the origami plates more compact, reducing their conductivity. The conductance of a DNA origami plate on top of a solid-state nanopore is determined by the two competing effects: bending of the DNA origami plate that reduces the current and separation of the DNA origami layers that increases the current. The latter is produced by the electro-osmotic flow and is reversible at the time scale of a hundred nanoseconds. The conductance of a DNA origami object is found to depend on its orientation, reaching maximum when the electric field aligns with the direction of the DNA helices. Our work demonstrates feasibility of programming the electrical properties of a self-assembled nanoscale object using DNA.
    ACS Nano 01/2015; 9(2). DOI:10.1021/nn505825z · 12.03 Impact Factor
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    ABSTRACT: Slowing down DNA translocation speed in a nanopore is essential to ensuring reliable resolution of individual bases. Thin membrane materials enhance spatial resolution but simultaneously reduce the temporal resolution as the molecules translocate far too quickly. In this study, the effect of exposed graphene layers on the transport dynamics of both single (ssDNA) and double-stranded DNA (dsDNA) through nanopores is examined. Nanopore devices with various combinations of graphene and Al2O3 dielectric layers in stacked membrane structures are fabricated. Slow translocations of ssDNA in nanopores drilled in membranes with layers of graphene are reported. The increased hydrophobic interactions between the ssDNA and the graphene layers could explain this phenomenon. Further confirmation of the hydrophobic origins of these interactions is obtained through reporting significantly faster translocations of dsDNA through these graphene layered membranes. Molecular dynamics simulations confirm the preferential interactions of DNA with the graphene layers as compared to the dielectric layer verifying the experimental findings. Based on our findings, we propose that the integration of multiple stacked graphene layers could slow down DNA enough to enable the identification of nucleobases.
    Advanced Functional Materials 12/2014; 25(6). DOI:10.1002/adfm.201403719 · 10.44 Impact Factor
  • Spencer Carson, James Wilson, Aleksei Aksimentiev, Meni Wanunu
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    ABSTRACT: Voltage-driven transport of double-stranded DNA through nanoscale pores holds much potential for applications in quantitative molecular biology and biotechnology, yet the microscopic details of translocation have proven to be challenging to decipher. Earlier experiments showed strong dependence of transport kinetics on pore size: fast regular transport in large pores (> 5 nm diameter), and slower yet heterogeneous transport time distributions in sub-5 nm pores, which imply a large positional uncertainty of the DNA in the pore as a function of the translocation time. In this work, we show that this anomalous transport is a result of DNA self-interaction, a phenomenon that is strictly pore-diameter dependent. We identify a regime in which DNA transport is regular, producing narrow and well-behaved dwell-time distributions that fit a simple drift-diffusion theory. Furthermore, a systematic study of the dependence of dwell time on DNA length reveals a single power-law scaling of 1.37 in the range of 35–20,000 bp. We highlight the resolution of our nanopore device by discriminating via single pulses 100 and 500 bp fragments in a mixture with >98% accuracy. When coupled to an appropriate sequence labeling method, our observation of smooth DNA translocation can pave the way for high-resolution DNA mapping and sizing applications in genomics.
    Biophysical Journal 11/2014; 107(10). DOI:10.1016/j.bpj.2014.10.017 · 3.83 Impact Factor
  • Manish Shankla, Aleksei Aksimentiev
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    ABSTRACT: Control over interactions with biomolecules holds the key to applications of graphene in biotechnology. One such application is nanopore sequencing, where a DNA molecule is electrophoretically driven through a graphene nanopore. Here we investigate how interactions of single-stranded DNA and a graphene membrane can be controlled by electrically biasing the membrane. The results of our molecular dynamics simulations suggest that electric charge on graphene can force a DNA homopolymer to adopt a range of strikingly different conformations. The conformational response is sensitive to even very subtle nucleotide modifications, such as DNA methylation. The speed of DNA motion through a graphene nanopore is strongly affected by the graphene charge: a positive charge accelerates the motion, whereas a negative charge arrests it. As a possible application of the effect, we demonstrate stop-and-go transport of DNA controlled by the charge of graphene. Such on-demand transport of DNA is essential for realizing nanopore sequencing.
    Nature Communications 10/2014; 5:5171. DOI:10.1038/ncomms6171 · 10.74 Impact Factor
  • C Maffeo, J Yoo, J Comer, D B Wells, B Luan, A Aksimentiev
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    ABSTRACT: Over the past ten years, the all-atom molecular dynamics method has grown in the scale of both systems and processes amenable to it and in its ability to make quantitative predictions about the behavior of experimental systems. The field of computational DNA research is no exception, witnessing a dramatic increase in the size of systems simulated with atomic resolution, the duration of individual simulations and the realism of the simulation outcomes. In this topical review, we describe the hallmark physical properties of DNA from the perspective of all-atom simulations. We demonstrate the amazing ability of such simulations to reveal the microscopic physical origins of experimentally observed phenomena. We also discuss the frustrating limitations associated with imperfections of present atomic force fields and inadequate sampling. The review is focused on the following four physical properties of DNA: effective electric charge, response to an external mechanical force, interaction with other DNA molecules and behavior in an external electric field.
    Journal of Physics Condensed Matter 09/2014; 26(41):413101. DOI:10.1088/0953-8984/26/41/413101 · 2.22 Impact Factor
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    Christopher Maffeo, Thuy T M Ngo, Taekjip Ha, Aleksei Aksimentiev
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    ABSTRACT: A simple coarse-grained model of single-stranded DNA (ssDNA) was developed, featuring only two sites per nucleotide that represent the centers of mass of the backbone and sugar/base groups. In the model, the interactions between sites are described using tabulated bonded potentials optimized to reproduce the solution structure of DNA observed in atomistic molecular dynamics simulations. Isotropic potentials describe nonbonded interactions, implicitly taking into account the solvent conditions to match the experimentally determined radius of gyration of ssDNA. The model reproduces experimentally measured force-extension dependence of an unstructured DNA strand across 2 orders of magnitude of the applied force. The accuracy of the model was confirmed by measuring the end-to-end distance of a dT14 fragment via FRET while stretching the molecules using optical tweezers. The model offers straightforward generalization to systems containing double-stranded DNA and DNA binding proteins.
    Journal of Chemical Theory and Computation 08/2014; 10(8):2891-2896. DOI:10.1021/ct500193u · 5.31 Impact Factor
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    Maxim Belkin, Shu-Han Chao, Gino Giannetti, Aleksei Aksimentiev
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    ABSTRACT: Local modulation of temperature has emerged as a new mechanism for regulation of molecular transport through nanopores. Predicting the effect of such modulations on nanopore transport requires simulation protocols capable of reproducing non-uniform temperature gradients observed in experiment. Conventional molecular dynamics (MD) method typically employs a single thermostat for maintaining a uniform distribution of temperature in the entire simulation domain, and, therefore, can not model local temperature variations. In this article, we describe a set of simulation protocols that enable modeling of nanopore systems featuring non-uniform distributions of temperature. First, we describe a method to impose a temperature gradient in all-atom MD simulations based on a boundary-driven non-equilibrium MD protocol. Then, we use this method to study the effect of temperature gradient on the distribution of ions in bulk solution (the thermophoretic effect). We show that DNA nucleotides exhibit differential response to the same temperature gradient. Next, we describe a method to directly compute the effective force of a thermal gradient on a prototypical biomolecule—a fragment of double-stranded DNA. Following that, we demonstrate an all-atom MD protocol for modeling thermophoretic effects in solid-state nanopores. We show that local heating of a nanopore volume can be used to regulate the nanopore ionic current. Finally, we show how continuum calculations can be coupled to a coarse-grained model of DNA to study the effect of local temperature modulation on electrophoretic motion of DNA through plasmonic nanopores. The computational methods described in this article are expected to find applications in rational design of temperature-responsive nanopore systems.
    Journal of Computational Electronics 07/2014; 13(4). DOI:10.1007/s10825-014-0594-8 · 1.37 Impact Factor
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    ABSTRACT: PEGylation, or addition of poly(ethylene glycol) chains to proteins, is widely used to improve delivery in pharmaceutical applications. Recent studies suggest that stabilization of a protein by PEG, and hence its proteolytic degradability, are sequence-dependent and require only short PEG chains. Here we connect stabilization by short PEG chains directly to the structural dynamics of the protein and PEG chain. We measured the stability of human Pin1 WW domain with PEG-4 at asparagine 19 for a full mutant cycle at two positions thought to influence PEG-protein interaction: Ser16Ala and Tyr23Phe. We then performed explicit solvent molecular dynamics simulations on all PEGylated and PEG-free mutants. The mutant cycle yields a non-additive stabilization effect where the pseudo wild type and double mutant are more stabilized relative to unPEGylated proteins than are the two single mutants. The simulation reveals why: the double mutant suffers loss of beta sheet structure, which PEGylation restores even though the PEG extends as a coil into the solvent. In contrast, in one of the single mutants PEG preferentially interacts with the protein surface while disrupting the interactions of its asparagine host with a nearby methionine side chain. Thus PEG attachment can stabilize a protein differentially depending on the local sequence, and either by interacting with the surface, or by extending into the solvent. A simulation with PEG-45 attached to asparagine 19 shows that PEG even can do both in the same context.
    The Journal of Physical Chemistry B 05/2014; 118(28). DOI:10.1021/jp502234s · 3.38 Impact Factor
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    ABSTRACT: Rectifying nanopores feature ion currents that are higher for voltages of one polarity compared to the currents recorded for corresponding voltages of the opposite polarity. Rectification of nanopores has been found to depend on the pore opening diameter and distribution of surface charges on the pore walls as well as pore geometry. Very little is known, however, on the dependence of ionic rectification on the type of transported ions of the same charge. We performed experiments with single conically shaped nanopores in a polymer film and recorded current–voltage curves in three electrolytes: LiCl, NaCl, and KCl. Rectification degrees of the pores, quantified as the ratio of currents recorded for voltages of opposite polarities, were the highest for KCl and the lowest for LiCl. The experimental observations could not be explained by a continuum modeling based on the Poisson–Nernst–Planck equations. All-atom molecular dynamics simulations revealed differential binding between Li+, Na+, and K+ ions and carboxyl groups on the pore walls, resulting in changes to both the effective surface charge of the nanopore and cation mobility within the pore.
    The Journal of Physical Chemistry C 04/2014; 118(18):9809–9819. DOI:10.1021/jp501492g · 4.84 Impact Factor
  • Hajin Kim, Jejoong Yoo, Aleksei Aksimentiev, Taekjip Ha
    Biophysical Journal 01/2014; 106(2):694a. DOI:10.1016/j.bpj.2013.11.3840 · 3.83 Impact Factor
  • Jejoong Yoo, Aleksei Aksimentiev
    Biophysical Journal 01/2014; 106(2):76a. DOI:10.1016/j.bpj.2013.11.496 · 3.83 Impact Factor
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    ABSTRACT: The conventional Poisson-Nernst-Planck equations do not account for the finite size of ions explicitly. This leads to solutions featuring unrealistically high ionic concentrations in the regions subject to external potentials, in particular, near highly charged surfaces. A modified form of the Poisson-Nernst-Planck equations accounts for steric effects and results in solutions with finite ion concentrations. Here, we evaluate numerical methods for solving the modified Poisson-Nernst-Planck equations by modeling electric field-driven transport of ions through a nanopore. We describe a novel, robust finite element solver that combines the applications of the Newton's method to the nonlinear Galerkin form of the equations, augmented with stabilization terms to appropriately handle the drift-diffusion processes. To make direct comparison with particle-based simulations possible, our method is specifically designed to produce solutions under periodic boundary conditions and to conserve the number of ions in the solution domain. We test our finite element solver on a set of challenging numerical experiments that include calculations of the ion distribution in a volume confined between two charged plates, calculations of the ionic current though a nanopore subject to an external electric field, and modeling the effect of a DNA molecule on the ion concentration and nanopore current.
    Communications in Computational Physics 01/2014; 15(1). DOI:10.4208/cicp.101112.100413a · 1.78 Impact Factor
  • Shu-Han Chao, Joshua Price, Aleksei Aksimentiev, Martin Gruebele
    Biophysical Journal 01/2014; 106(2):667a. DOI:10.1016/j.bpj.2013.11.3693 · 3.83 Impact Factor
  • Chen-Yu Li, Jejoong Yoo, Aleksei Aksimentiev
    Biophysical Journal 01/2014; 106(2):414a. DOI:10.1016/j.bpj.2013.11.2331 · 3.83 Impact Factor
  • Biophysical Journal 01/2014; 106(2):215a. DOI:10.1016/j.bpj.2013.11.1260 · 3.83 Impact Factor
  • Jejoong Yoo, Aleksei Aksimentiev
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    ABSTRACT: The DNA origami method permits folding of long single-stranded DNA into complex 3D structures with subnanometer precision. Transmission electron microscopy, atomic force microscopy, and recently cryo-EM tomography have been used to characterize the properties of such DNA origami objects, however their microscopic structures and dynamics have remained unknown. Here, we report the results of all-atom molecular dynamics simulations that characterized the structural and mechanical properties of DNA origami objects in unprecedented microscopic detail. When simulated in an aqueous environment, the structures of DNA origami objects depart from their idealized targets as a result of steric, electrostatic, and solvent-mediated forces. Whereas the global structural features of such relaxed conformations conform to the target designs, local deformations are abundant and vary in magnitude along the structures. In contrast to their free-solution conformation, the Holliday junctions in the DNA origami structures adopt a left-handed antiparallel conformation. We find the DNA origami structures undergo considerable temporal fluctuations on both local and global scales. Analysis of such structural fluctuations reveals the local mechanical properties of the DNA origami objects. The lattice type of the structures considerably affects global mechanical properties such as bending rigidity. Our study demonstrates the potential of all-atom molecular dynamics simulations to play a considerable role in future development of the DNA origami field by providing accurate, quantitative assessment of local and global structural and mechanical properties of DNA origami objects.
    Proceedings of the National Academy of Sciences 11/2013; 106(2). DOI:10.1073/pnas.1316521110 · 9.81 Impact Factor
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    ABSTRACT: Practical applications of solid-state nanopores for DNA detection and sequencing require the electrophoretic motion of DNA through the nanopores to be precisely controlled. Controlling the motion of single-stranded DNA presents a particular challenge, in part because of the multitude of conformations that a DNA strand can adopt in a nanopore. Through continuum, coarse-grained and atomistic modeling, we demonstrate that local heating of the nanopore volume can be used to alter the electrophoretic mobility and conformation of single-stranded DNA. In the nanopore systems considered, the temperature near the nanopore is modulated via a nanometer-size heater element that can be radiatively switched on and off. The local enhancement of temperature produces considerable stretching of the DNA fragment confined within the nanopore. Such stretching is reversible, so that the conformation of DNA can be toggled between compact (local heating is off) and extended (local heating is on) states. The effective thermophoretic force acting on single-stranded DNA in the vicinity of the nanopore is found to be sufficiently large (4-8~pN) to affect such changes in the DNA conformation. The local heating of the nanopore volume is observed to promote single-file translocation of DNA strands at transmembrane biases as low as 10~mV, which opens new avenues for using solid-state nanopores for detection and sequencing of DNA.
    ACS Nano 07/2013; 7(8). DOI:10.1021/nn403575n · 12.03 Impact Factor
  • Maxim Belkin, Aleksei Aksimentiev
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    ABSTRACT: Transport of ions, nucleic acids and other molecular species through pores in thin membranes is a process of fundamental importance to the biological function of a cell and practical applications in the field of molecular separation, filtering, and, recently, DNA sequencing. Various approaches to control the transport have been examined, including the effects of the geometry, charge and chemical functionalization of the nanopore surface. Thermophoresis in liquids, i.e. movement of molecules along a temperature gradient, was discovered more than a century ago and has already been employed in various applications, typically involving macroscopic systems. In this work, we explore the use of thermal gradients for regulation of nanoscale fluxes. Specifically, we use all-atom molecular dynamics simulations to examine the effect of thermal gradients on transport of ions, small organic solutes and long DNA molecules through solid-state nanopores. In our typical simulation, multiple thermostats are applied to different parts of the same simulation system, allowing steady-state temperature gradients to be established and the effective forces associated with the thermal gradients to be determined. The results of our simulations suggest that nanopore fluxes of molecular species can be regulated by means of thermal gradients. We expect our results to find applications in molecular separation and filtering technologies, nanofluidic electronics and nanopore sequencing of DNA.
  • Winston Timp, Jeffrey Comer, Aleksei Aksimentiev
    Biophysical Journal 01/2013; 104(2):211-. DOI:10.1016/j.bpj.2012.11.1195 · 3.83 Impact Factor
  • Jeffrey Comer, Anthony Ho, Aleksei Aksimentiev
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    ABSTRACT: Through all-atom molecular dynamics simulations, we explore the use of nanopores in thin synthetic membranes for detection and identification of DNA binding proteins. Reproducing the setup of a typical experiment, we simulate electric field driven transport of DNA-bound proteins through nanopores smaller in diameter than the proteins. As model systems, we use restriction enzymes EcoRI and BamHI specifically and nonspecifically bound to a fragment of dsDNA, and streptavidin and NeutrAvidin proteins bound to dsDNA and ssDNA via a biotin linker. Our simulations elucidate the molecular mechanics of nanopore-induced rupture of a protein-DNA complex, the effective force applied to the DNA-protein bond by the electrophoretic force in a nanopore, and the role of DNA-surface interactions in the rupture process. We evaluate the ability of the nanopore ionic current and the local electrostatic potential measured by an embedded electrode to report capture of DNA, capture of a DNA-bound protein, and rupture of the DNA-protein bond. We find that changes in the strain on dsDNA can reveal the rupture of a protein-DNA complex by altering both the nanopore ionic current and the potential of the embedded electrode. Based on the results of our simulations, we suggest a new method for detection of DNA binding proteins that utilizes peeling of a nicked double strand under the electrophoretic force in a nanopore.
    Electrophoresis 12/2012; 33(23). DOI:10.1002/elps.201200164 · 3.16 Impact Factor