@article {398, title = {Electro-Osmotic Flow Generation via a Sticky Ion Action}, journal = {ACS nano}, volume = {18}, year = {2024}, pages = {17521-17533}, chapter = {17521-17533}, abstract = {

Selective transport of ions through nanometer-sized pores is fundamental to cell biology and central to many technological processes such as water desalination and electrical energy storage. Conventional methods for generating ion selectivity include placement of fixed electrical charges at the inner surface of a nanopore through either point mutations in a protein pore or chemical treatment of a solid-state nanopore surface, with each nanopore type requiring a custom approach. Here, we describe a general method for transforming a nanoscale pore into a highly selective, anion-conducting channel capable of generating a giant electro-osmotic effect. Our molecular dynamics simulations and reverse potential measurements show that exposure of a biological nanopore to high concentrations of guanidinium chloride renders the nanopore surface positively charged due to transient binding of guanidinium cations to the protein surface. A comparison of four biological nanopores reveals the relationship between ion selectivity, nanopore shape, composition of the nanopore surface, and electro-osmotic flow. Guanidinium ions are also found to produce anion selectivity and a giant electro-osmotic flow in solid-state nanopores via the same mechanism. Our sticky-ion approach to generate electro-osmotic flow can have numerous applications in controlling molecular transport at the nanoscale and for detection, identification, and sequencing of individual proteins.

}, doi = {10.1021/acsnano.4c00829}, author = {Mehrafrooz, Behzad and Yu, Luning and Pandey, Laxmi and Siwy, Zuzanna S and Wanunu, Meni and Aksimentiev, Aleksei} } @article {384, title = {Unidirectional single-file transport of full-length proteins through a nanopore}, journal = {Nature Biotechnology}, volume = {41}, year = {2023}, month = {01/2023}, pages = {1130--1139}, abstract = {

The electrical current blockade of a peptide or protein threading through a nanopore can be used as a fingerprint of the molecule in biosensor applications. However, threading of full-length proteins has only been achieved using enzymatic unfolding and translocation. Here we describe an enzyme-free approach for unidirectional, slow transport of full-length proteins through nanopores. We show that the combination of a chemically resistant biological nanopore, α-hemolysin (narrowest part is \textasciitilde1.4\thinspacenm in diameter), and a high concentration guanidinium chloride buffer enables unidirectional, single-file protein transport propelled by an electroosmotic effect. We show that the mean protein translocation velocity depends linearly on the applied voltage and translocation times depend linearly on length, resembling the translocation dynamics of ssDNA. Using a supervised machine-learning classifier, we demonstrate that single-translocation events contain sufficient information to distinguish their threading orientation and identity with accuracies larger than 90\%. Capture rates of protein are increased substantially when either a genetically encoded charged peptide tail or a DNA tag is added to a protein.

}, issn = {1546-1696}, doi = {10.1038/s41587-022-01598-3}, url = {https://doi.org/10.1038/s41587-022-01598-3}, author = {Yu, Luning and Kang, Xinqi and Li, Fanjun and Mehrafrooz, Behzad and Makhamreh, Amr and Fallahi, Ali and Foster, Joshua C. and Aksimentiev, Aleksei and Chen, Min and Wanunu, Meni} } @article {370, title = {Fluorofoldamer-Based Salt- and Proton-Rejecting Artificial Water Channels for Ultrafast Water Transport.}, journal = {Nano Lett}, volume = {22}, year = {2022}, month = {2022 06 22}, pages = {4831-4838}, abstract = {

Here, we report on a novel class of fluorofoldamer-based artificial water channels (AWCs) that combines excellent water transport rate and selectivity with structural simplicity and robustness. Produced by a facile one-pot copolymerization reaction under mild conditions, the best-performing channel (AWC ) is an n-CH-decorated foldamer nanotube with an average channel length of 2.8 nm and a pore diameter of 5.2 {\r A}. AWC demonstrates an ultrafast water conduction rate of 1.4 {\texttimes} 10 HO/s per channel, outperforming the archetypal biological water channel, aquaporin 1, while excluding salts (i.e., NaCl and KCl) and protons. Unique to this class of channels, the inwardly facing C(sp2)-F atoms being the most electronegative in the periodic table are proposed as being critical to enabling the ultrafast and superselective water transport properties by decreasing the channel{\textquoteright}s cavity and enhancing the channel wall smoothness via reducing intermolecular forces with water molecules or hydrated ions.

}, keywords = {Aquaporins, Biological Transport, Protons, Sodium Chloride, Water}, issn = {1530-6992}, doi = {10.1021/acs.nanolett.2c01137}, author = {Shen, Jie and Roy, Arundhati and Joshi, Himanshu and Samineni, Laxmicharan and Ye, Ruijuan and Tu, Yu-Ming and Song, Woochul and Skiles, Matthew and Kumar, Manish and Aleksei Aksimentiev and Zeng, Huaqiang} } @article {385, title = {Trapping of protein cargo molecules inside DNA origami nanocages}, journal = {Nanoscale}, volume = {14}, year = {2022}, month = {11/2022}, pages = {18041{\textendash}18050}, abstract = {

The development of the DNA origami technique has directly inspired the idea of using three-dimensional DNA cages for the encapsulation and targeted delivery of drug or cargo molecules. The cages would be filled with molecules that would be released at a site of interest upon cage opening triggered by an external stimulus. Though different cage variants have been developed, efficient loading of DNA cages with freely-diffusing cargo molecules that are not attached to the DNA nanostructure and their efficient retention within the cages has not been presented. Here we address these challenges using DNA origami nanotubes formed by a double-layer of DNA helices that can be sealed with tight DNA lids at their ends. In a first step we attach DNA-conjugated cargo proteins to complementary target strands inside the DNA tubes. After tube sealing, the cargo molecules are released inside the cavity using toehold-mediated strand displacement by externally added invader strands. We show that DNA invaders are rapidly entering the cages through their DNA walls. Retention of \~{}70 kDa protein cargo molecules inside the cages was, however, poor. Guided by coarse-grained simulations of the DNA cage dynamics, a tighter sealing of the DNA tubes was developed which greatly reduced the undesired escape of cargo proteins. These improved DNA nanocages allow for efficient encapsulation of medium-sized cargo molecules while remaining accessible to small molecules that can be used to trigger reactions, including a controlled release of the cargo via nanocage opening.

}, doi = {10.1039/d2nr05356j}, author = {Merle Scherf and Florian Scheffler and Christopher Maffeo and Ulrich Kemper and Jingjing Ye and Aleksei Aksimentiev and Ralf Seidel and Uta Reibetanz} } @article {369, title = {DNA sequence and methylation prescribe the inside-out conformational dynamics and bending energetics of DNA minicircles.}, journal = {Nucleic Acids Res}, volume = {49}, year = {2021}, month = {11/2021}, pages = {11459-11475}, abstract = {

Eukaryotic genome and methylome encode DNA fragments{\textquoteright} propensity to form nucleosome particles. Although the mechanical properties of DNA possibly orchestrate such encoding, the definite link between {\textquoteright}omics{\textquoteright} and DNA energetics has remained elusive. Here, we bridge the divide by examining the sequence-dependent energetics of highly bent DNA. Molecular dynamics simulations of 42 intact DNA minicircles reveal that each DNA minicircle undergoes inside-out conformational transitions with the most likely configuration uniquely prescribed by the nucleotide sequence and methylation of DNA. The minicircles{\textquoteright} local geometry consists of straight segments connected by sharp bends compressing the DNA{\textquoteright}s inward-facing major groove. Such an uneven distribution of the bending stress favors minimum free energy configurations that avoid stiff base pair sequences at inward-facing major grooves. Analysis of the minicircles{\textquoteright} inside-out free energy landscapes yields a discrete worm-like chain model of bent DNA energetics that accurately account for its nucleotide sequence and methylation. Experimentally measuring the dependence of the DNA looping time on the DNA sequence validates the model. When applied to a nucleosome-like DNA configuration, the model quantitatively reproduces yeast and human genomes{\textquoteright} nucleosome occupancy. Further analyses of the genome-wide chromatin structure data suggest that DNA bending energetics is a fundamental determinant of genome architecture.

}, keywords = {DNA Methylation, DNA, Circular, Molecular Dynamics Simulation, Nucleic Acid Conformation}, issn = {1362-4962}, doi = {10.1093/nar/gkab967}, author = {Yoo, Jejoong and Park, Sangwoo and Maffeo, Christopher and Ha, Taekjip and Aleksei Aksimentiev} } @article {356, title = {The emerging landscape of single-molecule protein sequencing technologies}, journal = {Nature Methods}, volume = {18}, year = {2021}, month = {06/2021}, chapter = {604-617}, abstract = {

Single-cell profiling methods have had a profound impact on the understanding of cellular heterogeneity. While genomes and transcriptomes can be explored at the single-cell level, single-cell profiling of proteomes is not yet established. Here we describe new single-molecule protein sequencing and identification technologies alongside innovations in mass spectrometry that will eventually enable broad sequence coverage in single-cell profiling. These technologies will in turn facilitate biological discovery and open new avenues for ultrasensitive disease diagnostics.

}, doi = {10.1038/s41592-021-01143-1}, url = {https://doi.org/10.1038/s41592-021-01143-1}, author = {Javier Antonio Alfaro and Peggy Bohl{\"a}nder and Mingjie Dai and Mike Filius and Cecil J. Howard and Xander F. van Kooten and Shilo Ohayon and Adam Pomorski and Sonja Schmid and Aleksei Aksimentiev and Eric V. Anslyn and Georges Bedran and Chan Cao and Mauro Chinappi and Etienne Coyaud and Cees Dekker and Gunnar Dittmar and Nicholas Drachman and Rienk Eelkema and David Goodlett and S{\'e}bastien Hentz and Umesh Kalathiya and Neil L. Kelleher and Ryan T. Kelly and Zvi Kelman and Sung Hyun Kim and Bernhard Kuster and David Rodriguez-Larrea and Stuart Lindsay and Giovanni Maglia and Edward M. Marcotte and John P. Marino and Christophe Masselon and Michael Mayer and Patroklos Samaras and Kumar Sarthak and Lusia Sepiashvili and Derek Stein and Meni Wanunu and Mathias Wilhelm and Peng Yin and Amit Meller and Chirlmin Joo} } @article {346, title = {Electrical unfolding of cytochrome during translocation through a nanopore constriction.}, journal = {Proceedings of the National Academy of Sciences}, volume = {118}, year = {2021}, month = {04/2021}, pages = {e2016262118}, abstract = {

Many small proteins move across cellular compartments through narrow pores. In order to thread a protein through a constriction, free energy must be overcome to either deform or completely unfold the protein. In principle, the diameter of the pore, along with the effective driving force for unfolding the protein, as well as its barrier to translocation, should be critical factors that govern whether the process proceeds via squeezing, unfolding/threading, or both. To probe this for a well-established protein system, we studied the electric-field-driven translocation behavior of cytochrome (cyt ) through ultrathin silicon nitride (SiN) solid-state nanopores of diameters ranging from 1.5 to 5.5 nm. For a 2.5-nm-diameter pore, we find that, in a threshold electric-field regime of \~{}30 to 100 MV/m, cyt is able to squeeze through the pore. As electric fields inside the pore are increased, the unfolded state of cyt is thermodynamically stabilized, facilitating its translocation. In contrast, for 1.5- and 2.0-nm-diameter pores, translocation occurs only by threading of the fully unfolded protein after it transitions through a higher energy unfolding intermediate state at the mouth of the pore. The relative energies between the metastable, intermediate, and unfolded protein states are extracted using a simple thermodynamic model that is dictated by the relatively slow (\~{}ms) protein translocation times for passing through the nanopore. These experiments map the various modes of protein translocation through a constriction, which opens avenues for exploring protein folding structures, internal contacts, and electric-field-induced deformability.

}, issn = {1091-6490}, doi = {10.1073/pnas.2016262118}, author = {Tripathi, Prabhat and Benabbas, Abdelkrim and Mehrafrooz, Behzad and Yamazaki, Hirohito and Aleksei Aksimentiev and Champion, Paul M and Wanunu, Meni} } @article {341, title = {Translocation of DNA through Ultrathin Nanoslits}, journal = {Advanced Materials}, volume = {33}, year = {2021}, month = {02/2021}, pages = {2007682}, chapter = {2007682}, abstract = {

2D nanoslit devices, where two crystals with atomically flat surfaces are separated by only a few nanometers, have attracted considerable attention because their tunable control over the confinement allows for the discovery of unusual transport behavior of gas, water, and ions. Here, the passage of double-stranded DNA molecules is studied through nanoslits fabricated from exfoliated 2D materials, such as graphene or hexagonal boron nitride, and the DNA polymer behavior is examined in this tight confinement. Two types of events are observed in the ionic current: long current blockades that signal DNA translocation and short spikes where DNA enters the slits but withdraws. DNA translocation events exhibit three distinct phases in their current-blockade traces{\textemdash}loading, translation, and exit. Coarse-grained molecular dynamics simulation allows the different polymer configurations of these phases to be identified. DNA molecules, including folds and knots in their polymer structure, are observed to slide through the slits with near-uniform velocity without noticeable frictional interactions of DNA with the confining graphene surfaces. It is anticipated that this new class of 2D-nanoslit devices will provide unique ways to study polymer physics and enable lab-on-a-chip biotechnology.

}, keywords = {2D nanoslits, biopolymers, DNA translocation, graphene, Nanofluidics}, doi = {https://doi.org/10.1002/adma.202007682}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.202007682}, author = {Yang, Wayne and Radha, Boya and Choudhary, Adnan and You, Yi and Mettela, Gangaiah and Geim, Andre K. and Aleksei Aksimentiev and Keerthi, Ashok and Dekker, Cees} } @article {334, title = {Molecular dynamics simulations of DNA--DNA and DNA--protein interactions}, journal = {Current Opinion in Structural Biology}, volume = {64}, year = {2020}, month = {10/2020}, pages = {88--96}, chapter = {88}, abstract = {

The all-atom molecular dynamics method can characterize the molecular-level interactions in DNA and DNA--protein systems with unprecedented resolution. Recent advances in computational technologies have allowed the method to reveal the unbiased behavior of such systems at the microseconds time scale, whereas enhanced sampling approaches have matured enough to characterize the interaction free energy with quantitative precision. Here, we describe recent progress toward increasing the realism of such simulations by refining the accuracy of the molecular dynamics force field, and we highlight recent application of the method to systems of outstanding biological interest.

}, doi = {https://doi.org/10.1016/j.sbi.2020.06.007}, url = {https://doi.org/10.1016/j.sbi.2020.06.007}, author = {Jejoong Yoo and David Winogradoff and Aleksei Aksimentiev} } @article {320, title = {Polyhydrazide-based organic nanotubes as extremely efficient and highly selective artificial iodide channels}, journal = {Angewandte Chemie International Edition}, volume = {12}, year = {2020}, month = {02/2020}, pages = {4806-4813}, chapter = {4806}, abstract = {

We report herein a series of pore-containing polymeric nanotubes based on an H-bonded hydrazide backbone. Nanotubes of suitable lengths, possessing a hollow cavity of ~ 6.5 {\r A} in diameter, are found to mediate highly efficient transport of diverse types of anions, rather than cations, across the lipid membrane. Polymer channel 1a, having an averaged molecular weight of 18.2 KDa and 3.6 nm in helical height, exhibits the highest anion transport activities with iodide (EC50 = 0.042 micromolar\ or 0.028 mol \% relative to lipid) being transported 10 times more efficiently than chlorides (EC50 = 0.47 micromolar). Notably, even in the cholesterol-rich environment, iodide transport activity still remains high with EC50\ \ of 0.37 micromolar. Molecular dynamics simulation studies confirm that the channel is highly selective for anions and that such anion selectivity arises from a positive electrostatic potential of the central lumen rendered by the interior-pointing methyl groups.

}, doi = { https://doi.org/10.1002/anie.201916287}, author = {Roy, Arundhati and Joshi, Himanshu and Ye, Ruijuan and Shen, Jie and Chen, Feng and Aleksei Aksimentiev and Zeng, Huaqiang} } @article {319, title = {Rosette Nanotube Porins as Ion Selective Transporters and Single-Molecule Sensors}, journal = {Journal of the American Chemical Society}, volume = {142}, year = {2020}, month = {01/2020}, pages = {1680-1685}, chapter = {1680}, abstract = {

Rosette nanotubes (RNTs) are a class of materials formed by molecular self-assembly of a fused guanine-cytosine base (G^C base). An important feature of these self-assembled nanotubes is their precise atomic structure, intriguing for rational design and optimization as synthetic transmembrane porins. Here, we present experimental observations of ion transport across 1.1 nm inner diameter RNT porins (RNTPs) of various lengths in the range 5-200 nm. In a typical experiment, custom lipophilic RNTPs were first inserted into lipid vesicles; the vesicles then spontaneously fused with a planar lipid bilayer, which produced stepwise increases of ion current across the bilayer. Our measurements in 1 M KCl solution indicate ion transport rates of ~50 ions s-1 V-1 m, which for short channels amounts to conductance values of\  ~1 nS, commensurate with naturally occurring toxin channels such as α-hemolysin. Measurements of interaction times of α-cyclodextrin with RNTPs reveal two distinct unbinding time scales, which suggest that interactions of either face of α-cyclodextrin with the RNTP face are differentiable, backed with all-atom molecular dynamics simulations. Our results highlight the potential of RNTPs as self-assembled nonproteinaceous single-molecule sensors and selective nanofilters with tunable functionality through chemistry.

}, doi = {https://doi.org/10.1021/jacs.9b10993}, author = {Tripathi, Prabhat and Shuai, Liang and Joshi, Himanshu and Yamazaki, Hirohito and Fowle, William H and Aleksei Aksimentiev and Fenniri, Hicham and Wanunu, Meni} } @article {297, title = {Effect of temperature and hydrophilic ratio on the structure of poly(N-vinylcaprolactam)-block-poly(dimethylsiloxane)-block-poly(N-vinylcaprolactam) polymersomes}, journal = {ACS Applied Polymer Materials}, volume = {1}, year = {2019}, month = {04/2019}, pages = {722--736}, chapter = {722}, abstract = {

Nanosized polymeric vesicles (polymersomes) assembled from ABA triblock copolymers of poly(N-vinylcaprolactam)-poly(dimethylsiloxane)-poly(N-vinylcaprolactam) (PVCL-PDMS-PVCL) are a promising platform for biomedical applications, as the temperature-responsiveness of the PVCL blocks enables reversible vesicle shrinkage and permeability of the polymersome shell at elevated temperatures. Herein, we explore the effects of molecular weight, polymer block weight ratios, and temperature on the structure of these polymersomes via electron microscopy, dynamic light scattering, small angle neutron scattering (SANS), and all-atom molecular dynamic methods. We show that the shell structure and overall size of the polymersome can be tuned by varying the hydrophilic (PVCL) weight fraction of the polymer: at room temperature, polymers of smaller hydrophilic ratios form larger vesicles that have thinner shells, whereas polymers with higher PVCL content exhibit interchain aggregation of PVCL blocks within the polymersome shell above 50 {\textdegree}C. Model fitting and model-free analysis of the SANS data reveals that increasing the mass ratio of PVCL to the total copolymer weight from 0.3 to 0.56 reduces the temperature-induced change in vesicle diameter by a factor of 3 while simultaneously increasing the change in shell thickness by a factor of 1.5. Finally, by analysis of the shell structures and overall size of polymersomes with various PVCL weight ratios and those without temperature-dependent polymer components, we bring into focus the mechanism of temperature-triggered drug release reported in a previous study. This work provides new fundamental perspectives on temperature-responsive polymersomes and elucidates important structure-property relationships of their constituent polymers.

}, doi = {10.1021/acsapm.8b00259}, url = {https://pubs.acs.org/doi/pdf/10.1021/acsapm.8b00259}, author = {Yiming Yang and Aaron Alford and Kozlovskaya, Veronika and Zhao, Shidi and Joshi, Himanshu and Kim, Eunjung and Qian, Shuo and Urban, Volker and Cropek, Donald and Aleksei Aksimentiev and Kharlampieva, Eugenia} } @article {292, title = {Sequence-Dependent DNA Condensation as a Driving Force of DNA Phase Separation}, journal = {Nucleic Acids Research}, volume = {46}, year = {2018}, month = {10/2018}, pages = {9401--9413}, abstract = {

The physical properties of DNA have been suggested to play a central role in spatio-temporal organization of eukaryotic chromosomes. Experimental correlations have been established between the local nucleotide content of DNA and the frequency of inter- and intra-chromosomal contacts but the underlying physical mechanism remains unknown. Here, we combine fluorescence resonance energy transfer (FRET) measurements, precipitation assays, and molecular dynamics simulations to characterize the effect of DNA nucleotide content, sequence, and methylation on inter-DNA association and its correlation with DNA looping. First, we show that the strength of DNA condensation mediated by poly-lysine peptides as a reduced model of histone tails depends on the DNA{\textquoteright}s global nucleotide content but also on the local nucleotide sequence, which turns out to be qualitatively same as the condensation by spermine. Next, we show that the presence and spatial arrangement of C5 methyl groups determines the strength of inter-DNA attraction, partially explaining why RNA resists condensation. Interestingly, multi-color single molecule FRET measurements reveal strong anti-correlation between DNA looping and DNA{\textendash}DNA association, suggesting that a common biophysical mechanism underlies them. We propose that the differential affinity between DNA regions of varying sequence pattern may drive the phase separation of chromatin into chromosomal subdomains.

}, doi = {10.1093/nar/gky639 }, author = {Hyunju Kang and Jejoong Yoo and Hong Soo Lee and Byeong-Kwon Sohn and Seung-Won Lee and Wenjie Ma and Jung-Min Kee and Aleksei Aksimentiev and Hajin Kim} } @article {286, title = {A synthetic enzyme built from DNA flips 10$^{7}$ lipids per second in biological membranes}, journal = {Nature Communications}, volume = {9}, year = {2018}, month = {07/2018}, pages = {2426}, abstract = {

Mimicking enzyme function and increasing performance of naturally evolved proteins is one of the most challenging and intriguing aims of nanoscience. Here, we employ DNA nanotechnology to design a synthetic enzyme that substantially outperforms its biological archetypes. Consisting of only eight strands, our DNA nanostructure spontaneously inserts into biological membranes by forming a toroidal pore that connects the membrane{\textquoteright}s inner and outer leaflets. The membrane insertion catalyzes spontaneous transport of lipid molecules between the bilayer leaflets, rapidly equilibrating the lipid composition. Through a combination of microscopic simulations and fluorescence microscopy we find the lipid transport rate catalyzed by the DNA nanostructure exceeds 107 molecules per second, which is three orders of magnitude higher than the rate of lipid transport catalyzed by biological enzymes. Furthermore, we show that our DNA-based enzyme can control the composition of human cell membranes, which opens new avenues for applications of membrane-interacting DNA systems in medicine.

}, keywords = {Computational biophysics, DNA nanostructures, Membrane biophysics, Nanobiotechnology}, doi = {10.1038/s41467-018-04821-5}, url = {http://www.nature.com/articles/s41467-018-04821-5}, author = {Ohmann, Alexander and Li, Chen-Yu and Maffeo, Christopher and Al Nahas, Kareem and Baumann, Kevin N. and G{\"o}pfrich, Kerstin and Yoo, Jejoong and Keyser, Ulrich F. and Aleksei Aksimentiev} } @article {282, title = {New tricks for old dogs: Improving the accuracy of biomolecular force fields by pair-specific corrections to non-bonded interactions}, journal = {Physical Chemistry Chemical Physics}, volume = {20}, year = {2018}, month = {03/2018}, pages = {8432-8449}, abstract = {

In contrast to ordinary polymers, the vast majority of biological macromolecules adopt highly ordered three-dimensional structures that define their functions. The key to folding of a biopolymer into a unique 3D structure or to assembly of several biopolymers into a functional unit is a delicate balance between the attractive and repulsive forces that also makes such self-assembly reversible under physiological conditions. The all-atom molecular dynamics (MD) method has emerged as a powerful tool for studies of individual biomolecules and their functional assemblies, encompassing systems of ever increasing complexity. However, advances in parallel computing technology have outpaced development of the underlying theoretical models{\textemdash}the molecular force fields, pushing the MD method into untested territory. Recent tests of the MD method have found the most commonly used molecular force fields to be out of balance, overestimating attractive interactions between charged and hydrophobic groups, which can promote artificial aggregation in MD simulations of multi-component protein, nucleic acid, and lipid systems. One route to improving the force fields is through the NBFIX corrections method, in which the intermolecular forces are calibrated against experimentally measured quantities such as osmotic pressure by making atom pair-specific adjustments to the non-bonded interactions. In this article, we review development of the NBFIX corrections to the AMBER and CHARMM force fields and discuss their implications for MD simulations of electrolyte solutions, dense DNA systems, Holliday junctions, protein folding, and lipid bilayer membranes.

}, doi = {10.1039/C7CP08185E}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @inbook {277, title = {A Practical Guide to Molecular Dynamics Simulations of DNA Origami Systems}, booktitle = {DNA Nanotechology: Methods and Protocols}, series = {Methods in Molecular Biology}, volume = {1811}, year = {2018}, pages = {209-229}, publisher = {Humana Press}, organization = {Humana Press}, edition = {2}, chapter = {A Practical Guide to Molecular Dynamics Simulations of DNA Origami Systems}, address = {New York}, abstract = {

The DNA origami method exploits the self-assembly property of nucleic acids to build diverse nanoscale systems. The all-atom molecular dynamics (MD) method has emerged as a powerful computational tool for atomic-resolution characterization of the in situ structure and physical properties of DNA origami objects. This chapter provides step-by-step instructions for building atomic-scale models of DNA origami systems, using the MD method to simulate the models, and performing basic analyses of the resulting MD trajectories.\ 

}, issn = {978-1-4939-8581-4}, doi = {10.1007/978-1-4939-8582-1_15}, url = {https://link.springer.com/protocol/10.1007/978-1-4939-8582-1_15}, author = {Jejoong Yoo and Chen-Yu Li and Scott Michael Slone and Christopher Maffeo and Aleksei Aksimentiev}, editor = {Giampaolo Zuccheri} } @article {239, title = {Refined Parameterization of Nonbonded Interactions Improves Conformational Sampling and Kinetics of Protein Folding Simulations}, journal = {Journal of Physical Chemistry Letters}, volume = {7}, year = {2016}, month = {09/2016}, pages = {3812{\textendash}3818}, chapter = {3812}, abstract = {

Recent advances in computational technology have enabled brute-force molecular dynamics (MD) simulations of protein folding using physics-based molecular force fields. The extensive sampling of protein conformations afforded by such simulations revealed, however, considerable compaction of the protein conformations in the unfolded state, which is inconsistent with experiment. Here, we show that a set of surgical corrections to nonbonded interactions between amine nitrogen{\textendash}carboxylate oxygen and aliphatic carbon{\textendash}carbon atom pairs can considerably improve the realism of protein folding simulations. Specifically, we show that employing our corrections in \~{}500 μs all-atom replica-exchange MD simulations of the WW domain and villin head piece proteins increases the size of the denatured proteins{\textquoteright} conformations and does not destabilize the native conformations of the proteins. In addition to making the folded conformations a global minimum of the respective free energy landscapes at room temperature, our corrections also make the free energy landscape smoother, considerably accelerating the folding kinetics and, hence, reducing the computational expense of a protein folding simulation.

}, doi = {10.1021/acs.jpclett.6b01747}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @article {237, title = {Large-Conductance Transmembrane Porin Made from DNA Origami}, journal = {ACS Nano}, volume = {10}, year = {2016}, month = {08/2016}, pages = {8207--8214}, abstract = {

DNA nanotechnology allows for the creation of three-dimensional structures at nanometer scale. Here, we use DNA to build the largest synthetic pore in a lipid membrane to date, approaching the dimensions of the nuclear pore complex and increasing the pore-area and the conductance tenfold compared to previous man-made channels. In our design, nineteen cholesterol-tags anchor a megadalton funnel-shaped DNA origami porin in a lipid bilayer membrane (see equilibration trajectory, require login to nanoHUB). Confocal imaging and ionic current recordings reveal spontaneous insertion of the DNA porin into the lipid membrane, creating a transmembrane pore of tens of nanosiemens conductance (see ionic current trajectory). All-atom molecular dynamics simulations characterize the conductance mechanism at the atomic level and independently confirm the DNA porins{\textquoteright} large ionic conductance.

}, doi = {10.1021/acsnano.6b03759}, author = {Kerstin G{\"o}pfrich* and Chen-Yu Li* and Maria Ricci and Satya Prathyusha Bhamidimarri and Jejoong Yoo and Bertalan Gyenes and Alexander Ohmann and Mathias Winterhalter and Aleksei Aksimentiev and Ulrich F Keyser} } @article {218, title = {Improved model of hydrated calcium ion for molecular dynamics simulations using classical biomolecular force fields}, journal = {Biopolymers}, volume = {105}, year = {2016}, month = {07/2016}, pages = {752-763}, chapter = {752}, abstract = {
Calcium ions (Ca2+) play key roles in various fundamental biological processes such as cell signaling and brain function . Molecular dynamics (MD) simulations have been used to study such interactions, however, the accuracy of the Ca2+ models provided by the standard M D force fields has not been rigorously tested. Here, we assess the performance of the Ca2+ models from the most popular classical force fields AMBER and CHARMM by computing the osmotic pressure of model compounds and the free energy of DNA{\textendash}DNA inter act i on s. In the simulations performed using the two standard models, Ca2+ ions are seen to form artificial clusters with chloride, acetate, and phosphate species; the osmotic pressure of CaAc2and CaCl2solutions is a small fraction of the experimental values for both force fields. Using the standard parameterization of Ca2+ ions in the simulations of Ca2+-mediated DNA-DNA interact ions leads to qualitatively wrong outcomes: both AMBER and CHARMM simulations suggest strong inter-DNA attraction whereas, in experiment, DNA molecules repel one another. The artificial attraction of Ca2+to DNA phosphate is strong enough to affect the direction of the electric field-driven translocation of DNA through a solid-state nanopore. To address these shortcomings of the standard Ca2+ model, we introduce a custom model of a hydrated Ca2+ ion and show that using our model brings the results of the above MD simulations in quantitative agreement with experiment. Our improved model of Ca2+ can be readily applied to MD simulations of various biomolecular systems, including nucleic acids, proteins and lipid bilayer membranes.
}, doi = {10.1002/bip.22868}, author = {Jejoong Yoo and James Wilson and Aleksei Aksimentiev} } @article {236, title = {Ion Channels Made from a Single Membrane-Spanning DNA Duplex}, journal = {Nano Letters}, volume = {16}, year = {2016}, month = {06/2016}, pages = {4665--4669}, abstract = {

Due to their hollow interior, transmembrane channels are capable of opening up pathways for ions across lipid membranes of living cells. Here, we demonstrate ion conduction induced by a single DNA duplex that lacks a hollow central channel. Decorated with six porpyrin-tags, our duplex is designed to span lipid membranes. Combining electrophysiology measurements with all-atom molecular dynamics simulations, we elucidate the microscopic conductance pathway\ (see\ water channel\ trajectory, require login to nanoHUB). Ions flow (see ion transport\ trajectory)\ at the DNA-lipid interface as the lipid head groups tilt towards the amphiphilic duplex forming a toroidal pore filled with water and ions. Ionic current traces produced by the DNA-lipid channel show well-defined insertion steps, closures and gating similar to those observed for traditional protein channels or synthetic pores. Ionic conductances obtained through simulations and experiments are in excellent quantitative agreement. The conductance mechanism realized here, with the smallest possible DNA-based ion channel, offers a route to design a new class of synthetic ion channels with maximum simplicity.

}, doi = {10.1021/acs.nanolett.6b02039}, author = {Kerstin G{\"o}pfrich and Chen-Yu Li and Iwona Mames and Satya Prathyusha Bhamidimarri and Maria Ricci and Jejoong Yoo and Adam Mames and Alexander Ohmann and Mathias Winterhalter and Eugen Stulz and Aleksei Aksimentiev and Ulrich F Keyser} } @article {226, title = {Molecular mechanics of DNA bricks: in situ structure, mechanical properties and ionic conductivity}, journal = {New Journal of Physics}, volume = {18}, year = {2016}, month = {05/2016}, pages = {055012}, abstract = {

The DNA bricks method exploits self-assembly of short DNA fragments to produce custom three-dimensional objects with subnanometer precision. In contrast to DNA origami, the DNA brick method permits a variety of different structures to be realized using the same library of DNA strands. As a consequence of their design, however, assembled DNA brick structures have fewer interhelical connections in comparison to equivalent DNA origami structures. Although the overall shape of the DNA brick objects has been characterized and found to conform to the features of the target designs, the microscopic properties of DNA brick objects remain yet to be determined. Here, we use the all-atom molecular dynamics method to directly compare the structure, mechanical properties and ionic conductivity of DNA brick and DNA origami structures different only by internal connectivity of their consistituent DNA strands. In comparison to equivalent DNA origami structures, the DNA brick structures are found to be less rigid and less dense and have a larger cross-section area normal to the DNA helix direction. At the microscopic level, the junction in the DNA brick structures are found to be right-handed, similar to the structure of individual Holliday junctions (HJ) in solution, which contrasts with the left-handed structure of HJ in DNA origami. Subject to external electric field, a DNA brick plate is more leaky to ions than an equivalent DNA origami plate because of its lower density and larger cross-section area. Overall, our results indicate that the structures produced by the DNA brick method are fairly similar in their overall appearance to those created by the DNA origami method but are more compliant when subject to external forces, which likely is a consequence of their single crossover design.

}, doi = {10.1088/1367-2630/18/5/055012}, url = {http://dx.doi.org/10.1088/1367-2630/18/5/055012}, author = {Scott Michael Slone and Chen-Yu Li and Jejoong Yoo and Aleksei Aksimentiev} } @article {247, title = {Water Mediates Recognition of DNA Sequence via Ionic Current Blockade in a Biological Nanopore}, journal = {ACS Nano}, volume = {10}, year = {2016}, month = {04/2016}, pages = {4644{\textendash}4651}, abstract = {

Electric field-driven translocation of DNA strands through biological nanopores has been shown to produce blockades of the nanopore ionic current that depend on the nucleotide composition of the strands. Coupling a biological nanopore MspA to a DNA processing enzyme has made DNA sequencing \ via\ measurement of \ ionic current blockades \ possible. Nevertheless, the physical mechanism enabling the DNA sequence readout has remained undetermined. Here, we report the results of all-atom molecular dynamics simulations that elucidated the physical mechanism of ionic current blockades in the biological nanopore MspA. We find that the amount of water displaced from the nanopore by the DNA strand determines the nanopore ionic current, whereas the steric and base-stacking properties of the DNA nucleotides determine the amount of water displaced. \ Unexpectedly, we \ find the effective force on DNA in MspA to undergo large fluctuations, which may produce insertion errors in the DNA sequence readout.

}, doi = {10.1021/acsnano.6b00940}, author = {Swati Bhattacharya and Jejoong Yoo and Aleksei Aksimentiev} } @article {214, title = {De Novo Reconstruction of DNA Origami Structures through Atomistic Molecular Dynamics Simulation}, journal = {Nucleic Acids Research}, volume = {44}, year = {2016}, month = {04/2016}, pages = {3013-3019}, chapter = {3013}, abstract = {

The DNA origami method has brought nanometer-precision fabrication to molecular biology labs, offering myriads of potential applications in the fields of synthetic biology, biomolecular medicine, molecular computation, etc. Advancing the method further requires controlling self-assembly down to the atomic scale. Here we demonstrate a computational method that allows the equilibrium structure of a large, complex DNA origami object to be determined to atomic resolution. Through direct comparison with the results of cryo-electron microscopy, we demonstrate de novo reconstruction of a 4.7 megadalton pointer structure by means of fully atomistic molecular dynamics simulations. Furthermore, we show that elastic network-guided simulations performed without solvent can yield similar accuracy at a fraction of the computational cost, making this method an attractive approach for prototyping and validation of self-assembled DNA nanostructures.

}, doi = {10.1093/nar/gkw155}, url = {http://nar.oxfordjournals.org/content/early/2016/03/14/nar.gkw155}, author = {Christopher Maffeo and Jejoong Yoo and Aleksei Aksimentiev} } @article {211, title = {Direct evidence for sequence-dependent attraction between double-stranded DNA controlled by methylation}, journal = {Nature Communications}, volume = {7}, year = {2016}, month = {03/2016}, pages = {11045}, abstract = {

Although proteins mediate highly ordered DNA organization\ in vivo, theoretical studies suggest that homologous DNA duplexes can preferentially associate with one another even in the absence of proteins. Here we combine molecular dynamics simulations with single-molecule fluorescence resonance energy transfer experiments to examine the interactions between duplex DNA in the presence of spermine, a biological polycation. We find that AT-rich DNA duplexes associate more strongly than GC-rich duplexes, regardless of the sequence homology. Methyl groups of thymine acts as a steric block, relocating spermine from major grooves to interhelical regions, thereby increasing DNA{\textendash}DNA attraction. Indeed, methylation of cytosines makes attraction between GC-rich DNA as strong as that between AT-rich DNA. Recent genome-wide chromosome organization studies showed that remote contact frequencies are higher for AT-rich and methylated DNA, suggesting that direct DNA{\textendash}DNA interactions that we report here may play a role in the chromosome organization and gene regulation.

}, doi = {10.1038/ncomms11045}, author = {Jejoong Yoo and Hajin Kim and Aleksei Aksimentiev and Taekjip Ha} } @article {212, title = {The structure and intermolecular forces of DNA condensates}, journal = {Nucleic Acids Research}, volume = {44}, year = {2016}, pages = {2036{\textendash}2046}, abstract = {

Spontaneous assembly of DNA molecules into compact structures is ubiquitous in biological systems. Experiment has shown that polycations can turn electrostatic self-repulsion of DNA into attraction, yet the physical mechanism of DNA condensation has remained elusive. Here, we report the results of atomistic molecular dynamics simulations that elucidated the microscopic structure of dense DNA assemblies and the physics of interactions that makes such assemblies possible. Reproducing the setup of the DNA condensation experiments, we measured the internal pressure of DNA arrays as a function of the DNA{\textendash}DNA distance, showing a quantitative agreement between the results of our simulations and the experimental data. Analysis of the MD trajectories determined the DNA{\textendash}DNA force in a DNA condensate to be pairwise, the DNA condensation to be driven by electrostatics of polycations and not hydration, and the concentration of bridging cations, not adsorbed cations, to determine the magnitude and the sign of the DNA{\textendash}DNA force. Finally, our simulations quantitatively characterized the orientational correlations of DNA in DNA arrays as well as diffusive motion of DNA and cations.

}, doi = {10.1093/nar/gkw081}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @article {210, title = {Effect of Cytosine Modifications on DNA Flexibility and Nucleosome Mechanical Stability}, journal = {Nature Communications}, volume = {7}, year = {2016}, pages = {10813}, chapter = {10813}, abstract = {

Cytosine can undergo modifications, forming 5-methylcytosine (5-mC) and its oxidized products 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). Despite their importance as epigenetic markers and as central players in cellular processes, it is not well understood how these modifications influence physical properties of DNA and chromatin. Here we report a comprehensive survey of the effect of cytosine modifications on DNA flexibility. We find that even a single copy of 5-fC increases DNA flexibility markedly. 5-mC reduces and 5-hmC enhances flexibility, and 5-caC does not have a measurable effect. Molecular dynamics simulations show that these modifications promote or dampen structural fluctuations, likely through competing effects of base polarity and steric hindrance, without changing the average structure. The increase in DNA flexibility increases the mechanical stability of the nucleosome and vice versa, suggesting a gene regulation mechanism where cytosine modifications change the accessibility of nucleosomal DNA through their effects on DNA flexibility.

}, doi = {10.1038/ncomms10813}, author = {Thuy Ngo and Jejoong Yoo and Dai, Q and Zhang, Q and He, C and Aleksei Aksimentiev and Taekjip Ha} } @article {209, title = {Improved Parameterization of Amine{\textendash}Carboxylate and Amine{\textendash}Phosphate Interactions for Molecular Dynamics Simulations Using the CHARMM and AMBER Force Fields}, journal = {Journal of Chemical Theory and Computation}, volume = {12}, year = {2016}, pages = {430{\textendash}443}, abstract = {

Over the past decades, molecular dynamics (MD) simulations of biomolecules have become a mainstream biophysics technique. As the length and time scales amenable to the MD method increase, shortcomings of the empirical force fields, which have been developed and validated using relatively short simulations of small molecules, become apparent. One common artifact is aggregation of water-soluble biomolecules driven by artificially strong charge{\textendash}charge interactions. Here, we report a systematic atom pair-specific refinement of Lennard-Jones parameters (NBFIX) describing amine{\textendash}carboxylate and amine{\textendash}phosphate interactions, which bring MD simulations of basic peptide-mediated nucleic acid assemblies and lipid bilayer membranes into better agreement with experimental data. As our refinement does not affect the existing parametrization of bonded interactions or alter the solvation free energies, it improves the realism of an MD simulation without introducing additional artifacts.

}, doi = {10.1021/acs.jctc.5b00967}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @article {206, title = {Molecular Dynamics of Membrane-Spanning DNA Channels: Conductance Mechanism, Electro-Osmotic Transport, and Mechanical Gating}, journal = {The Journal of Physical Chemistry Letters}, volume = {6}, year = {2015}, month = {11/2015}, pages = {4680-4687}, abstract = {

DNA self-assembly has emerged as a new paradigm for design of biomimetic membrane channels. Several experimental groups have already demonstrated assembly and insertion of DNA channels into lipid bilayer membranes; however, the structure of the channels and their conductance mechanism have remained undetermined. Here, we report the results of molecular dynamics simulations that characterized the biophysical properties of the DNA membrane channels with atomic precision. We show that, while overall remaining stable, the local structure of the channels undergoes considerable fluctuations, departing from the idealized design. The transmembrane ionic current flows both through the central pore of the channel as well as along the DNA walls and through the gaps in the DNA structure. Surprisingly, we find that the conductance of DNA channels depend on the membrane tension, making them potentially suitable for force-sensing applications. Finally, we show that electro-osmosis governs the transport of druglike molecules through the DNA channels.

}, doi = {10.1021/acs.jpclett.5b01964}, url = {http://dx.doi.org/10.1021/acs.jpclett.5b01964}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @article {LI2015, title = {Ionic Conductivity, Structural Deformation, and Programmable Anisotropy of DNA Origami in Electric Field}, journal = {ACS Nano}, volume = {9}, year = {2015}, note = {PMID: 25623807}, month = {01/2015}, pages = {1420-1433}, 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 Mg2+\ 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.

}, doi = {10.1021/nn505825z}, url = {http://dx.doi.org/10.1021/nn505825z}, author = {Li, Chen-Yu and Hemmig, Elisa A. and Kong, Jinglin and Yoo, Jejoong and Hern{\'a}ndez-Ainsa, Silvia and Keyser, Ulrich F. and Aleksei Aksimentiev} } @article {139, title = {Close encounters with DNA}, journal = {J Phys Condens Matter}, volume = {26}, year = {2014}, month = {10/2014}, pages = {413101}, 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.

}, keywords = {Review}, issn = {1361-648X}, doi = {10.1088/0953-8984/26/41/413101}, author = {Christopher Maffeo and Yoo, J and Jeffrey Comer and Wells, D B and Luan, B and Aleksei Aksimentiev} } @article {90, title = {In situ structure and dynamics of DNA origami determined through molecular dynamics simulations.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {12/2013}, pages = {20099-104}, 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.

}, keywords = {DNA, Single-Stranded, Models, Molecular, Molecular Dynamics Simulation, Nanotechnology, Nucleic Acid Conformation, Water}, issn = {1091-6490}, doi = {10.1073/pnas.1316521110}, author = {Yoo, Jejoong and Aleksei Aksimentiev} } @article {25, title = {Competitive binding of cations to duplex DNA revealed through molecular dynamics simulations}, journal = {J Phys Chem B}, volume = {116}, year = {2012}, month = {2012 Nov 1}, pages = {12946-54}, abstract = {

The concept of "ion atmosphere" is prevalent in both theoretical and experimental studies of nucleic acid systems, yet the spatial arrangement and the composition of ions in the ion atmosphere remain elusive, in particular when several ionic species (e.g., Na(+), K(+), and Mg(2+)) compete to neutralize the charge of a nucleic acid polyanion. Complementing the experimental study of Bai and co-workers (J. Am. Chem. Soc.2007, 129, 14981), here we characterize ion atmosphere around double-stranded DNA through all-atom molecular dynamics simulations. We demonstrate that our improved parametrization of the all-atom model can quantitatively reproduce the experimental ion-count data. Our simulations determine the size of the ion atmosphere, the concentration profiles of ionic species competing to neutralize the DNA charge, and the sites of the cations{\textquoteright} preferential binding at the surface of double-stranded DNA. We find that the effective size of the ion atmosphere depends on both the bulk concentration and valence of ions: increasing either reduces the size of the atmosphere. Near DNA, the concentration of Mg(2+) is strongly enhanced compared to monovalent cations. Within the DNA grooves, the relative concentrations of cations depend on their bulk values. Nevertheless, the total charge of competing cations buried in the DNA grooves is constant and compensates for about ~30\% of the total DNA charge.

}, keywords = {Base Pairing, Base Sequence, Binding, Competitive, Cations, DNA, Molecular Dynamics Simulation, Phosphates, Static Electricity}, issn = {1520-5207}, doi = {10.1021/jp306598y}, author = {Yoo, Jejoong and Aleksei Aksimentiev} } @article {18, title = {Modeling and simulation of ion channels}, journal = {Chem Rev}, volume = {112}, year = {2012}, month = {2012 Dec 12}, pages = {6250-6284}, abstract = {

Transport of ions through pores in membranes is a process of fundamental importance to cell biology. In living organisms, such transport is facilitated by ion channels that utilize the ionic flux to perform diverse biological functions, such as cell{\textendash}cell communication and signaling, osmotic stress response, muscle contraction, etc. The action of ion channels is responsible for most of what we (humans) perceive as reality in the form of sound, smell, sight, taste, and touch and forms the physiological basis for thought. Biomimetic ion channels are ubiquitous in engineering, with application ranging from water desalination to fuel cells. Here, we review efforts to model and simulate ion channels that occurred within the past 10 years.

}, keywords = {Review}, issn = {1520-6890}, doi = {10.1021/cr3002609}, author = {Christopher Maffeo and Bhattacharya, Swati and Yoo, Jejoong and David B Wells and Aleksei Aksimentiev} } @article {91, title = {Improved Parametrization of Li+, Na+, K+, and Mg2+ Ions for All-Atom Molecular Dynamics Simulations of Nucleic Acid Systems}, journal = {The Journal of Physical Chemistry Letters}, volume = {3}, year = {2012}, pages = {45-50}, abstract = {

Atomic-scale modeling of compacted nucleic acids has the ability to reveal the inner workings of spectacular biomolecular machines, yet the outcome of such modeling efforts sensitively depends on the accuracy of the underlying computational models. Our molecular dynamics simulations of an array of 64 parallel duplex DNA revealed considerable artifacts of cation-DNA phosphate interactions in CHARMM and AMBER parameter sets: both the DNA arrangement and the pressure inside the DNA arrays were found to be in considerable disagreement with experiment. To improve the models, we fine-tuned van der Waals interaction parameters for specific ion pairs to reproduce experimental osmotic pressure of binary electrolyte solutions of biologically relevant ions. Repeating the DNA array simulations using our parameters produced results consistent with experiment. Our improved parametrization can be directly applied to molecular dynamics simulations of various charged biomolecular systems, including nucleic acids, proteins, and lipid bilayer membranes.

}, issn = {1948-7185}, doi = {10.1021/jz201501a}, url = {http://pubs.acs.org/doi/abs/10.1021/jz201501a}, author = {Yoo, Jejoong and Aleksei Aksimentiev} } @article {60, title = {Stretching and unzipping nucleic acid hairpins using a synthetic nanopore}, journal = {Nucleic Acids Res}, volume = {36}, year = {2008}, month = {2008 Mar}, pages = {1532-41}, abstract = {

We have explored the electromechanical properties of DNA by using an electric field to force single hairpin molecules to translocate through a synthetic pore in a silicon nitride membrane. We observe a threshold voltage for translocation of the hairpin through the pore that depends sensitively on the diameter and the secondary structure of the DNA. The threshold for a diameter 1.5 < d < 2.3 nm is V > 1.5 V, which corresponds to the force required to stretch the stem of the hairpin, according to molecular dynamics simulations. On the other hand, for 1.0 < d < 1.5 nm, the threshold voltage collapses to V < 0.5 V because the stem unzips with a lower force than required for stretching. The data indicate that a synthetic nanopore can be used like a molecular gate to discriminate between the secondary structures in DNA.

}, keywords = {Biological Transport, DNA, Electric Conductivity, Membranes, Artificial, Models, Molecular, Nanostructures, Nucleic Acid Conformation, Silicon Compounds}, issn = {1362-4962}, doi = {10.1093/nar/gkm1017}, author = {Zhao, Q and Jeffrey Comer and Valentin Dimitrov and Yemenicioglu, S and Aleksei Aksimentiev and Gregory Timp} } @article {54, title = {Computer modeling in biotechnology: a partner in development}, journal = {Methods Mol Biol}, volume = {474}, year = {2008}, month = {2008}, pages = {181-234}, abstract = {

Computational modeling can be a useful partner in biotechnology, in particular, in nanodevice engineering. Such modeling guides development through nanoscale views of biomolecules and devices not available through experimental imaging methods. We illustrate the role of computational modeling, mainly of molecular dynamics, through four case studies: development of silicon bionanodevices for single molecule electrical recording, development of carbon nano-tube-biomolecular systems as in vivo sensors, development of lipoprotein nanodiscs for assays of single membrane proteins, and engineering of oxygen tolerance into the enzyme hydrogenase for photosynthetic hydrogen gas production. The four case studies show how molecular dynamics approaches were adapted to the specific technical uses through (i) multi-scale extensions, (ii) fast quantum chemical force field evaluation, (iii) coarse graining, and (iv) novel sampling methods. The adapted molecular dynamics simulations provided key information on device behavior and revealed development opportunities, arguing that the "computational microscope" is an indispensable nanoengineering tool.

}, keywords = {Biosensing Techniques, Biotechnology, Computational Biology, Computer Simulation, Models, Molecular, Nanostructures}, issn = {1064-3745}, doi = {10.1007/978-1-59745-480-3_11}, author = {Aleksei Aksimentiev and Robert Brunner and Cohen, Jordi and Jeffrey Comer and Eduardo Cruz-Ch{\'u} and Hardy, David and Rajan, Aruna and Amy Y Shih and G Sigalov and Yin, Ying and Klaus Schulten} }