@article {395, title = {A Marcus-Type Inverted Region in the Translocation Kinetics of a Knotted Protein}, journal = {The Journal of Physical Chemistry Letters}, year = {2023}, month = {11/2023}, pages = {10719-10726}, abstract = {

Knotted proteins are rare but important species, yet how their complex topologies affect their physical properties is not fully understood. Here we combine single molecule nanopore experiments and all-atom MD simulations to study the electric-field-driven unfolding during the translocation through a model pore of individual protein knots important for methylating tRNA. One of these knots shows an unusual behavior that resembles the behavior of electrons hopping between two potential surfaces: as the electric potential driving the translocation reaction is increased, the rate eventually plateaus or slows back down in the {\textquotedblleft}Marcus inverted regime{\textquotedblright}. Our results shed light on the influence of topology in knotted proteins on their forced translocation through a pore connecting two electrostatic potential wells.

}, doi = {10.1021/acs.jpclett.3c02183}, url = {https://doi.org/10.1021/acs.jpclett.3c02183}, author = {Tripathi, Prabhat and Mehrafrooz, Behzad and Aksimentiev, Aleksei and Jackson, Sophie E. and Gruebele, Martin and Wanunu, Meni} } @article {394, title = {Molecular Determinants of Current Blockade Produced by Peptide Transport Through a Nanopore}, journal = {ACS Nanosci. Au}, year = {2023}, month = {11/2023}, abstract = {

The nanopore sensing method holds the promise of delivering a single molecule technology for identification of biological proteins, direct detection of post-translational modifications, and perhaps de novo determination of a protein{\textquoteright}s amino acid sequence. The key quantity measured in such nanopore sensing experiments is the magnitude of the ionic current passing through a nanopore blocked by a polypeptide chain. Establishing a relationship between the amino acid sequence of a peptide fragment confined within a nanopore and the blockade current flowing through the nanopore remains a major challenge for realizing the nanopore protein sequencing. Using the results of all-atom molecular dynamics simulations, here we compare nanopore sequencing of DNA with nanopore sequencing of proteins. We then delineate the factors affecting the blockade current modulation by the peptide sequence, showing that the current can be determined by (i) the steric footprint of an amino acid, (ii) its interactions with the pore wall, (iii) the local stretching of a polypeptide chain, and (iv) the local enhancement of the ion concentration at the nanopore constriction. We conclude with a brief discussion of the prospects for purely computational prediction of the blockade currents.

}, doi = {10.1021/acsnanoscienceau.3c00046}, author = {Jingqian Liu and Aleksei Aksimentiev} } @article {377, title = {Multi-resolution simulation of DNA transport through large synthetic nanostructures.}, journal = {Phys Chem Chem Phys}, volume = {24}, year = {2022}, month = {2022 Feb 02}, pages = {2706-2716}, abstract = {

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

}, keywords = {Biological Transport, DNA, Electricity, Molecular Dynamics Simulation, Nanopores}, issn = {1463-9084}, doi = {10.1039/d1cp04589j}, author = {Choudhary, Adnan and Maffeo, Christopher and Aleksei Aksimentiev} } @article {365, title = {Multiple rereads of single proteins at single{\textendash}amino acid resolution using nanopores}, journal = {Science}, volume = {374}, year = {2021}, month = {11/2021}, pages = {1509{\textendash}1513}, abstract = {

A proteomics tool capable of identifying single proteins would be important for cell biology research and applications. Here, we demonstrate a nanopore-based single-molecule peptide reader sensitive to single{\textendash}amino acid substitutions within individual peptides. A DNA-peptide conjugate was pulled through the biological nanopore MspA by the DNA helicase Hel308. Reading the ion current signal through the nanopore enabled discrimination of single{\textendash}amino acid substitutions in single reads. Molecular dynamics simulations showed these signals to result from size exclusion and pore binding. We also demonstrate the capability to {\textquotedblleft}rewind{\textquotedblright} peptide reads, obtaining numerous independent reads of the same molecule, yielding an error rate of \<10-6\ in single amino acid variant identification. These proof-of-concept experiments constitute a promising basis for the development of a single-molecule protein fingerprinting and analysis technology.

}, doi = {10.1021/acs.nanolett.1c04203}, author = {Brinkerhoff, Henry and Kang, Albert SW and Liu, Jingqian and Aleksei Aksimentiev and Dekker, Cees} } @article {363, title = {Membrane Activity of a DNA-Based Ion Channel Depends on the Stability of Its Double-Stranded Structure}, journal = {Nano Letters}, volume = {21}, year = {2021}, month = {11/2021}, pages = {9789{\textendash}9796}, chapter = {9789}, abstract = {

DNA nanotechnology has emerged as a promising method for designing spontaneously inserting and fully controllable synthetic ion channels. However, both insertion efficiency and stability of existing DNA-based membrane channels leave much room for improvement. Here, we demonstrate an approach to overcoming the unfavorable DNA{\textendash}lipid interactions that hinder the formation of a stable transmembrane pore. Our all-atom MD simulations and experiments show that the insertion-driving cholesterol modifications can cause fraying of terminal base pairs of nicked DNA constructs, distorting them when embedded in a lipid bilayer. Importantly, we show that DNA nanostructures with no backbone discontinuities form more stable conductive pores and insert into membranes with higher efficiency than the equivalent nicked constructs. Moreover, lack of nicks allows the design and maintenance of membrane-spanning helices in a tilted orientation within the lipid bilayer. Thus, reducing the conformational degrees of freedom of the DNA nanostructures enables better control over their function as synthetic ion channels.

}, keywords = {DNA structures, lipid membranes, nicks, protein-mimicking, synthetic ion channel, tilt}, doi = {10.1021/acs.nanolett.1c03791}, url = {https://pubs.acs.org/doi/10.1021/acs.nanolett.1c03791}, author = {Morzy, Diana and Joshi, Himanshu and Sandler, Sarah E. and Aleksei Aksimentiev and Keyser, Ulrich F.} } @article {355, title = {The Manipulation of the Internal Hydrophobicity of FraC Nanopores Augments Peptide Capture and Recognition}, journal = {ACS Nano}, year = {2021}, month = {06/2021}, abstract = {

The detection of analytes and the sequencing of DNA using biological nanopores have seen major advances over recent years. The analysis of proteins and peptides with nanopores, however, is complicated by the complex physicochemical structure of polypeptides and the lack of understanding of the mechanism of capture and recognition of polypeptides by nanopores. In this work, we show that introducing aromatic amino acids at precise positions within the lumen of α-helical fragaceatoxin C (FraC) nanopores increased the capture frequency of peptides and largely improved the discrimination among peptides of similar size. Molecular dynamics simulations determined the sensing region of the nanopore, elucidated the microscopic mechanism enabling accurate characterization of the peptides\ via\ ionic current blockades in FraC, and characterized the effect of the pore modification on peptide discrimination. This work provides insights to improve the recognition and to augment the capture of peptides by nanopores, which is important for developing a real-time and single-molecule size analyzer for peptide recognition and identification.

}, doi = {10.1021/acsnano.0c09958}, url = {https://doi.org/10.1021/acsnano.0c09958}, author = {Florian Leonardus Rudolfus Lucas and Kumar Sarthak and Erica Mariska Lenting and David Coltan and Nieck Jordy van der Heide and Roderick Corstiaan Abraham Versloot and Aleksei Aksimentiev and Giovanni Maglia} } @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 {336, title = {Molecular Transport across the Ionic Liquid-Aqueous Electrolyte Interface in a MoS2 Nanopore}, journal = {ACS Appl. Mater. Interfaces}, volume = {12}, year = {2020}, month = {05/2020}, pages = {26624 - 26634}, chapter = {26624}, abstract = {

Nanopore sequencing of DNA has been enabled by the use of a biological enzyme to thread DNA through an engineered biological nanopore while recording the ionic current flowing through the nanopore. Efforts to realize a similar concept using a solid-state nanopore have been met with several technical challenges, one of which is the high speed of DNA translocation and the other the low ionic current contrast among individual nucleotides. A promising avenue to addressing both problems is using an ionic liquid to slow DNA translocation and a tiny nanopore in the MoS2 membrane to distinguish individual nucleotides. The physical mechanisms enabling these technical advances have remained elusive. Here, we characterize the ion and DNA transport through the ionic liquid/aqueous electrolyte interface, with and without a MoS2 nanopore, using the all-atom molecular dynamics method. We find that the partial miscibility of the ionic liquid and the aqueous electrolyte considerably alters the physics of the nanopore translocation process. Thus, the interface of the two phases generates a contact potential of 600 mV, the ionic current is dominated by the motion of ionic liquid molecules through the aqueous solution phase, and the DNA nucleotides exhibit preferential partitioning into the aqueous electrolyte, which leads to spontaneous transport of DNA polymers from the ionic liquid to the aqueous solution compartment in the absence of external voltage bias. The complex physics of the two-phase nanopore system offers a multitude of opportunities for extending the functionality of nanopore-sensing platforms.

}, doi = {10.1021/acsami.0c04523}, author = {Manish Shankla and Aleksei Aksimentiev} } @article {325, title = {MrDNA: a multi-resolution model for predicting the structure and dynamics of DNA systems}, journal = {Nucleic Acids Research}, year = {2020}, abstract = {

Although the field of structural DNA nanotechnology has been advancing with an astonishing pace, de novo design of complex 3D nanostructures and functional devices remains a laborious and time-consuming process. One reason for that is the need for multiple cycles of experimental characterization to elucidate the effect of design choices on the actual shape and function of the self-assembled objects. Here, we demonstrate a multi-resolution simulation framework, mrdna, that, in 30 min\ or less, can produce an atomistic-resolution structure of a self-assembled DNA nanosystem. We demonstrate fidelity of our mrdna framework through direct comparison of the simulation results with the results of cryo-electron microscopy (cryo-EM) reconstruction of multiple 3D DNA origami objects. Furthermore, we show that our approach can characterize an ensemble of conformations adopted by dynamic DNA nanostructures, the equilibrium structure and dynamics of DNA objects constructed using off-lattice self-assembly principles, i.e.\ wireframe DNA objects, and to study the properties of DNA objects under a variety of environmental conditions, such as applied electric field. Implemented as an open source Python package, our framework can be extended by the community and integrated with DNA design and molecular graphics tools.

}, doi = {10.1093/nar/gkaa200}, url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkaa200/5814051}, author = {Maffeo, Christopher and Aleksei Aksimentiev} } @article {294, title = {Molecular Mechanism of Spontaneous Nucleosome Unraveling}, journal = {Journal of Molecular Biology}, volume = {431}, year = {2019}, month = {11/2018}, pages = {323--335}, abstract = {

Meters of DNA wrap around histone proteins to form nucleosomes and fit inside the micron-diameter nucleus. For the genetic information encoded in the DNA to become available for transcription, replication and repair, the DNA--histone assembly must be disrupted. Experiment has indicated that the outer stretches of nucleosomal DNA "breathe"\ by spontaneously detaching from and reattaching to the histone core. Here, we report direct observation of spontaneous DNA breathing in atomistic molecular dynamics simulations, detailing a microscopic mechanism of the DNA breathing process. According to our simulations, the outer stretches of nucleosomal DNA detach in discrete steps involving five or ten base pairs, with the detachment process being orchestrated by the motion of several conserved histone residues. The inner stretches of nucleosomal DNA are found to be more stably associated with the histone core by more abundant nonspecific DNA--protein contacts, providing a microscopic interpretation of nucleosome unraveling experiments. The CG content of nucleosomal DNA is found to anticorrelate with the extent of unwrapping, supporting the possibility that AT-rich segments may signal the start of transcription by forming less stable nucleosomes.

}, doi = {10.1016/j.jmb.2018.11.013}, author = {David Winogradoff and Aleksei Aksimentiev} } @article {296, title = {Molecular Mechanisms of DNA Replication and Repair Machinery: Insights from Microscopic Simulations}, journal = {Advanced Theory and Simulations}, volume = {2}, year = {2019}, month = {02/2019}, pages = {1800191}, abstract = {

Reproduction, the hallmark of biological activity, requires making an accurate copy of the genetic material to allow the progeny to inherit parental traits. In all living cells, the process of DNA replication is carried out by a concerted action of multiple protein species forming a loose protein{\textendash}nucleic acid complex, the replisome. Proofreading and error correction generally accompany replication but also occur independently, safeguarding genetic information through all phases of the cell cycle. Advances in biochemical characterization of intracellular processes, proteomics, and the advent of single-molecule biophysics have brought about a treasure trove of information awaiting to be assembled into an accurate mechanistic model of the DNA replication process. This review describes recent efforts to model elements of DNA replication and repair processes using computer simulations, an approach that has gained immense popularity in many areas of molecular biophysics but has yet to become mainstream in the DNA metabolism community. It highlights the use of diverse computational methods to address specific problems of the fields and discusses unexplored possibilities that lie ahead for the computational approaches in these areas.

}, keywords = {coarse-grained simulation, DNA damage, DNA repair, homologous recombination, Molecular dynamics, nucleic acids, QM/MM, replisome}, doi = {10.1002/adts.201800191}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adts.201800191}, author = {Maffeo, Christopher and Chou, Han-Yi and Aleksei Aksimentiev} } @article {273, title = {Molecular mechanism of DNA association with single-stranded DNA binding protein}, journal = {Nucleic Acids Research}, volume = {45}, year = {2017}, month = {12/2017}, pages = {12125{\textendash}12139}, chapter = {12125}, abstract = {

During DNA replication, the single-stranded DNA binding protein (SSB) wraps single-stranded DNA (ssDNA) with high affinity to protect it from degradation and prevent secondary structure formation. Although SSB binds ssDNA tightly, it can be repositioned along ssDNA to follow the advancement of the replication fork. Using all-atom molecular dynamics simulations, we characterized the molecular mechanism of ssDNA association with SSB. Placed in solution, ssDNA{\textendash}SSB assemblies were observed to change their structure spontaneously; such structural changes were suppressed in the crystallographic environment. Repeat simulations of the SSB{\textendash}ssDNA complex under mechanical tension revealed a multitude of possible pathways for ssDNA to come off SSB punctuated by prolonged arrests at reproducible sites at the SSB surface. Ensemble simulations of spontaneous association of short ssDNA fragments with SSB detailed a three-dimensional map of local affinity to DNA; the equilibrium amount of ssDNA bound to SSB was found to depend on the electrolyte concentration but not on the presence of the acidic tips of the SSB tails. Spontaneous formation of ssDNA bulges and their diffusive motion along SSB surface was directly observed in multiple 10-{\textmu}s-long simulations. Such reptation-like motion was confined by DNA binding to high-affinity spots, suggesting a two-step mechanism for SSB diffusion.

}, doi = {10.1093/nar/gkx917}, url = {http://dx.doi.org/10.1093/nar/gkx917}, author = {Maffeo, Christopher and Aleksei Aksimentiev} } @article {252, title = {Modulation of Molecular Flux Using a Graphene Nanopore Capacitor}, journal = {The Journal of Physical Chemistry B}, volume = {121}, year = {2017}, month = {02/2017}, pages = {3724-3733}, chapter = {3724}, abstract = {

Modulation of ionic current flowing through nanoscale pores is one of the fundamental biological processes. Inspired by nature, nanopores in synthetic solid-state membranes are being developed to enable rapid analysis of biological macromolecules and to serve as elements of nanofludic circuits. Here, we \ theoretically investigate ion and water transport through a graphene-insulator-graphene membrane containing a single, electrolyte-filled nanopore. By means of all-atom molecular dynamics simulations we show \ that the charge state of such a graphene nanopore capacitor \ can \ regulate both the selectivity and the magnitude of the nanopore ionic current. At a fixed transmembrane bias, the ionic current can be switched from being carried by an equal mixture of cations and anions to being carried almost exclusively by either cationic or anionic species, depending on the the sign of the charge assigned to both plates of the capacitor. \  Assigning the plates of the capacitor opposite sign charges can either increase the nanopore current or reduce it substantially, depending on the polarity of the \ bias driving the transmembrane current. Facilitated by dynamic inversion of the nanopore surface charge, such ionic current modulations are found to occur despite the physical dimensions of the nanopore being an order of magnitude larger than the screening length of the electrolyte. The \ ionic current rectification is accompanied by a pronounced electro-osmotic effect that can transport neutral molecules such as proteins and drugs across the solid-state membrane and thereby serve as an interface between electronic and chemical signals.

}, issn = {1520-6106}, doi = {10.1021/acs.jpcb.6b10574}, author = {Manish Shankla and Aleksei Aksimentiev} } @article {250, title = {Mechanical Trapping of DNA in a Double-Nanopore System}, journal = {Nano Letters}, volume = {16}, year = {2016}, month = {11/2016}, pages = {8021-8028 }, abstract = {

Nanopores have become ubiquitous components of systems for single-molecule manipulation and detection, in particular DNA sequencing where electric field driven translocation of DNA through a nanopore is used to read out the DNA molecule. Here, we present a double-pore system where two nanopores are drilled in parallel through the same solid-state membrane, which offers new opportunities for DNA manipulation. Our experiments and molecular dynamics simulations show that simultaneous electrophoretic capture of a DNA molecule by the two nanopores mechanically traps the molecule, increasing its residence time within the nanopores by orders of magnitude. Remarkably, by using two unequal-sized nanopores, the pore of DNA entry and exit can be discerned from the ionic current blockades, and the translocation direction can be precisely controlled by small differences in the effective force applied to DNA. The mechanical arrest of DNA translocation using a double-pore system can be straightforwardly integrated into any solid-state nanopore platform, including those using optical or transverse-current readouts.

}, doi = {10.1021/acs.nanolett.6b04642}, author = {Sergii Pud and Shu-Han Chao and Maxim Belkin and Daniel Verschueren and Teun Huijben and Casper van Engelenburg and Cees Dekker and Aleksei Aksimentiev} } @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 {BELK2016, title = {Molecular Dynamics Simulation of DNA Capture and Transport in Heated Nanopores}, journal = {ACS Applied Materials and Interfaces}, volume = {8}, year = {2016}, note = {PMID: 26963065}, month = {05/2016}, pages = {12599{\textendash}12608}, type = {Research}, abstract = {

The integration of local heat sources with solid-state nanopores offers new means for controlling the transmembrane transport of charged biomacromolecules. In the case of electrophoretic transport of DNA, recent experimental studies revealed unexpected temperature dependences of the DNA capture rate, the DNA translocation velocity, and the ionic current blockades produced by the presence of DNA in the nanopore.\  Here, we report the results of all-atom molecular dynamics (MD) simulations that elucidated the effect of temperature on the key microscopic processes governing\  electric field-driven transport of DNA through nanopores. Mimicking the experimental setup, we simulated the capture and subsequent translocation of short DNA duplexes through a locally heated nanopore at several temperature and electrolyte conditions. The temperature dependence of ion mobility at the DNA surface was found to cause\  the dependence of the relative conductance blockades on temperature. To the first order, the effective force on DNA in the nanopore was found to be independent of temperature, despite a considerable reduction of solution viscosity. The temperature dependence of the solution viscosity was found to make DNA translocations faster for a\  uniformly heated system but not in the case of local heating that does not affect viscosity of solution surrounding the untranslocated part of the molecule. Increasing solution temperature was also found to reduce the lifetime of bonds formed between cations and DNA. Using a flow suppression algorithm, we were able to separate the effects of electro-osmotic flow and direct ion binding, finding the reduced durations of DNA--ion bonds to increase, albeit weakly, the effective force experienced by DNA in an electric field. Unexpectedly, our simulations revealed a considerable temperature dependence of\  solvent velocity at the DNA surface---slip velocity, an effect that can alter hydrodynamic coupling between the motion of DNA and the surrounding fluid.

}, doi = {10.1021/acsami.6b00463}, url = {http://dx.doi.org/10.1021/acsami.6b00463}, author = {Maxim Belkin 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 {133, title = {Modeling thermophoretic effects in solid-state nanopores}, journal = {Journal of Computational Electronics}, volume = {13}, year = {2014}, pages = {826-838}, publisher = {Springer US}, 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 {\textemdash} 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.

}, keywords = {Boundary-driven MD, Molecular dynamics, Nanofluidics, Non-equilibrium MD, Plasmonic heating, Soret coefficient, Thermodiffusion, Thermophoresis}, issn = {1569-8025}, doi = {10.1007/s10825-014-0594-8}, url = {http://dx.doi.org/10.1007/s10825-014-0594-8}, author = {Maxim Belkin and Shu-Han Chao and Giannetti, Gino 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 {26, title = {Molecular dynamics study of MspA arginine mutants predicts slow DNA translocations and ion current blockades indicative of DNA sequence}, journal = {ACS Nano}, volume = {6}, year = {2012}, month = {2012 Aug 28}, pages = {6960-8}, abstract = {

The protein nanopore Mycobacteria smegmatis porin A (MspA), can be used to sense individual nucleotides within DNA, potentially enabling a technique known as nanopore sequencing. In this technique, single-stranded DNA electrophoretically moves through the nanopore and results in an ionic current that is nucleotide-specific. However, with a high transport velocity of the DNA within the nanopore, the ionic current cannot be used to distinguish signals within noise. Through extensive (~100 μs in total) all-atom molecular dynamics simulations, we examine the effect of positively charged residues on DNA translocation rate and the ionic current blockades in MspA. Simulation of several arginine mutations show a ~10-30 fold reduction of DNA translocation speed without eliminating the nucleotide induced current blockages. Comparison of our results with similar engineering efforts on a different nanopore (α-hemolysin) reveals a nontrivial effect of nanopore geometry on the ionic current blockades in mutant nanopores.

}, keywords = {Arginine, Base Sequence, Biosensing Techniques, Computer Simulation, Conductometry, DNA, Electric Conductivity, Ion Channel Gating, Models, Chemical, Models, Genetic, Models, Molecular, Molecular Sequence Data, Mutation, Porins, Sequence Analysis, DNA, Translocation, Genetic}, issn = {1936-086X}, doi = {10.1021/nn3019943}, author = {Bhattacharya, Swati and Derrington, Ian M and Pavlenok, Mikhail and Niederweis, Michael and Gundlach, Jens H and Aleksei Aksimentiev} } @article {28, title = {Microscopic Perspective on the Adsorption Isotherm of a Heterogeneous Surface}, journal = {J Phys Chem Lett}, volume = {2}, year = {2011}, month = {2011 Jul 2}, pages = {1804-1807}, abstract = {

Adsorption of dissolved molecules onto solid surfaces can be extremely sensitive to the atomic-scale properties of the solute and surface, causing difficulties for the design of fluidic systems in industrial, medical and technological applications. In this communication, we show that the Langmuir isotherm for adsorption of a small molecule to a realistic, heterogeneous surface can be predicted from atomic structures of the molecule and surface through molecular dynamics (MD) simulations. We highlight the method by studying the adsorption of dimethyl-methylphosphonate (DMMP) to amorphous silica substrates and show that subtle differences in the atomic-scale surface properties can have drastic effects on the Langmuir isotherm. The sensitivity of the method presented is sufficient to permit the optimization of fluidic devices and to determine fundamental design rules for controlling adsorption at the nanoscale.

}, issn = {1948-7185}, doi = {10.1021/jz200749d}, author = {Carr, Rogan and Jeffrey Comer and Ginsberg, Mark D and Aleksei Aksimentiev} } @article {39, title = {Modeling Pressure-Driven Transport of Proteins through a Nanochannel}, journal = {IEEE Trans Nanotechnol}, volume = {10}, year = {2011}, month = {2011 Jan}, pages = {75-82}, abstract = {

Reducing the size of a nanofluidic channel not only creates new opportunities for high-precision manipulation of biological macromolecules, but also makes the performance of the entire nanofluidic system more susceptible to undesirable interactions between the transported biomolecules and the walls of the channel. In this manuscript, we report molecular dynamics simulations of a pressure-driven flow through a silica nanochannel that characterized, with atomic resolution, adsorption of a model protein to its surface. Although the simulated adsorption of the proteins was found to be nonspecific, it had a dramatic effect on the rate of the protein transport. To determine the relative strength of the protein-silica interactions in different adsorbed states, we simulated flow-induced desorption of the proteins from the silica surface. Our analysis of the protein conformations in the adsorbed states did not reveal any simple dependence of the adsorption strength on the size and composition of the protein-silica contact, suggesting that the heterogeneity of the silica surface may be a important factor.

}, issn = {1536-125X}, author = {Carr, Rogan and Jeffrey Comer and Ginsberg, Mark D and Aleksei Aksimentiev} } @inbook {35, title = {Modeling nanopores for sequencing DNA}, booktitle = {DNA Nanotechnology: Methods and Protocols}, volume = {749}, year = {2011}, month = {2011}, pages = {317-358}, abstract = {

Using nanopores to sequence DNA rapidly and at a low cost has the potential to radically transform the field of genomic research. However, despite all the exciting developments in the field, sequencing DNA using a nanopore has yet to be demonstrated. Among the many problems that hinder development of the nanopore sequencing methods is the inability of current experimental techniques to visualize DNA conformations in a nanopore and directly relate the microscopic state of the system to the measured signal. We have recently shown that such tasks could be accomplished through computation. This chapter provides step-by-step instructions of how to build atomic scale models of biological and solid-state nanopore systems, use the molecular dynamics method to simulate the electric field-driven transport of ions and DNA through the nanopores, and analyze the results of such computational experiments.

}, keywords = {Base Sequence, Computer Simulation, DNA, Hemolysin Proteins, Models, Molecular, Molecular Conformation, Molecular Dynamics Simulation, Nanopores, Nanotechnology, Sequence Analysis, DNA}, issn = {1940-6029}, doi = {10.1007/978-1-61779-142-0_22}, author = {Jeffrey Comer and David B Wells and Aleksei Aksimentiev}, editor = {Giampaolo Zuccheri and Bruno Samori} } @inbook {145, title = {Modeling the Interface between Biological and Synthetic Components in Hybrid Nanosystems}, booktitle = {Simulations in Nanobiotechnology}, year = {2011}, pages = {43-60}, publisher = {CRC Press}, organization = {CRC Press}, chapter = {2}, abstract = {Hybrid structures that combine biological and inorganic materials are ubiquitous in the biosphere, from the carbonated hydroxyapatite that makes up the inorganic structure of bones to the calcium carbonate created by coral polyps and coralline algae that form the structure of coral reefs. The ability to design materials that are bio-compatible, or able to be incorporated into organisms without provoking an immune response, is important for medicine and therapeutics, for example, in prosthetics and implanted medical devices such as pacemakers. However, designing synthetic materials to interact favorably with biological components is made difficult by the fact that many biological processes, including immune response, are dictated by interactions betweeen biomolecules and their environment on the nanometer scale. Therefore, our ability to fabricate materials with nanometer precision would provide hope for a future in which man-made devices can easily interface with the biological world.}, issn = {9781439835043}, url = {http://www.crcpress.com/product/isbn/9781439835043}, author = {Carr, Rogan and Jeffrey Comer and Aleksei Aksimentiev}, editor = {Eom, Kilho} } @article {43, title = {Mechanical properties of a complete microtubule revealed through molecular dynamics simulation}, journal = {Biophys J}, volume = {99}, year = {2010}, month = {2010 Jul 21}, pages = {629-37}, abstract = {

Microtubules (MTs) are the largest type of cellular filament, essential in processes ranging from mitosis and meiosis to flagellar motility. Many of the processes depend critically on the mechanical properties of the MT, but the elastic moduli, notably the Young{\textquoteright}s modulus, are not directly revealed in experiment, which instead measures either flexural rigidity or response to radial deformation. Molecular dynamics (MD) is a method that allows the mechanical properties of single biomolecules to be investigated through computation. Typically, MD requires an atomic resolution structure of the molecule, which is unavailable for many systems, including MTs. By combining structural information from cryo-electron microscopy and electron crystallography, we have constructed an all-atom model of a complete MT and used MD to determine its mechanical properties. The simulations revealed nonlinear axial stress-strain behavior featuring a pronounced softening under extension, a possible plastic deformation transition under radial compression, and a distinct asymmetry in response to the two senses of twist. This work demonstrates the possibility of combining different levels of structural information to produce all-atom models suitable for quantitative MD simulations, which extends the range of systems amenable to the MD method and should enable exciting advances in our microscopic knowledge of biology.

}, keywords = {Biomechanical Phenomena, Microtubules, Molecular Dynamics Simulation, Protein Multimerization, Stress, Mechanical, Tubulin}, issn = {1542-0086}, doi = {10.1016/j.bpj.2010.04.038}, author = {David B Wells and Aleksei Aksimentiev} } @article {48, title = {Modeling Transport Through Synthetic Nanopores}, journal = {IEEE Nanotechnol Mag}, volume = {3}, year = {2009}, month = {2009 Mar}, pages = {20-28}, abstract = {

Nanopores in thin synthetic membranes have emerged as convenient tools for high-throughput single-molecule manipulation and analysis. Because of their small sizes and their ability to selectively transport solutes through otherwise impermeable membranes, nanopores have numerous potential applications in nanobiotechnology. For most applications, properties of the nanopore systems have to be characterize at the atomic level, which is currently beyond the limit of experimental methods. Molecular dynamics (MD) simulations can provide the desired information, however several technical challenges have to be met before this method can be applied to synthetic nanopore systems. Here, we highlight our recent work on modeling synthetic nanopores of the most common types. First, we describe a novel graphical tool for setting up all-atom systems incorporating inorganic materials and biomolecules. Next, we illustrate the application of the MD method for silica, silicon nitride, and polyethylene terephthalate nanopores. Following that, we describe a method for modeling synthetic surfaces using a bias potential. Future directions for tool development and nanopore modeling are briefly discussed at the end of this article.

}, issn = {1932-4510}, doi = {10.1109/MNANO.2008.931112}, author = {Aleksei Aksimentiev and Robert Brunner and Eduardo Cruz-Ch{\'u} and Jeffrey Comer and Klaus Schulten} } @article {50, title = {Microscopic mechanics of hairpin DNA translocation through synthetic nanopores}, journal = {Biophys J}, volume = {96}, year = {2009}, month = {2009 Jan}, pages = {593-608}, abstract = {

Nanoscale pores have proved useful as a means to assay DNA and are actively being developed as the basis of genome sequencing methods. Hairpin DNA (hpDNA), having both double-helical and overhanging coil portions, can be trapped in a nanopore, giving ample time to execute a sequence measurement. In this article, we provide a detailed account of hpDNA interaction with a synthetic nanopore obtained through extensive all-atom molecular dynamics simulations. For synthetic pores with minimum diameters from 1.3 to 2.2 nm, we find that hpDNA can translocate by three modes: unzipping of the double helix and--in two distinct orientations--stretching/distortion of the double helix. Furthermore, each of these modes can be selected by an appropriate choice of the pore size and voltage applied transverse to the membrane. We demonstrate that the presence of hpDNA can dramatically alter the distribution of ions within the pore, substantially affecting the ionic current through it. In experiments and simulations, the ionic current relative to that in the absence of DNA can drop below 10\% and rise beyond 200\%. Simulations associate the former with the double helix occupying the constriction and the latter with accumulation of DNA that has passed through the constriction.

}, keywords = {Cell Membrane Permeability, Computer Simulation, DNA, Ion Transport, Membrane Potentials, Membranes, Artificial, Microelectrodes, Microscopy, Electron, Transmission, Models, Molecular, Monte Carlo Method, Nanostructures, Nucleic Acid Conformation}, issn = {1542-0086}, doi = {10.1016/j.bpj.2008.09.023}, author = {Jeffrey Comer and Valentin Dimitrov and Zhao, Qian and Gregory Timp and Aleksei Aksimentiev} } @article {71, title = {Molecular dynamics simulations of proteins in lipid bilayers}, journal = {Curr Opin Struct Biol}, volume = {15}, year = {2005}, month = {2005 Aug}, pages = {423-31}, abstract = {

With recent advances in X-ray crystallography of membrane proteins promising many new high-resolution structures, molecular dynamics simulations will become increasingly valuable for understanding membrane protein function, as they can reveal the dynamic behavior concealed in the static structures. Dramatic increases in computational power, in synergy with more efficient computational methodologies, now allow us to carry out molecular dynamics simulations of any structurally known membrane protein in its native environment, covering timescales of up to 0.1 micros. At the frontiers of membrane protein simulations are ion channels, aquaporins, passive and active transporters, and bioenergetic proteins.

}, keywords = {Computer Simulation, Ion Channels, Lipid Bilayers, Membrane Proteins, Models, Molecular, Protein Conformation}, issn = {0959-440X}, doi = {10.1016/j.sbi.2005.07.007}, author = {Gumbart, James and Wang, Yi and Aleksei Aksimentiev and Tajkhorshid, Emad and Klaus Schulten} } @article {73, title = {Microscopic Kinetics of DNA Translocation through synthetic nanopores}, journal = {Biophys J}, volume = {87}, year = {2004}, month = {2004 Sep}, pages = {2086-97}, abstract = {

We have previously demonstrated that a nanometer-diameter pore in a nanometer-thick metal-oxide-semiconductor-compatible membrane can be used as a molecular sensor for detecting DNA. The prospects for using this type of device for sequencing DNA are avidly being pursued. The key attribute of the sensor is the electric field-induced (voltage-driven) translocation of the DNA molecule in an electrolytic solution across the membrane through the nanopore. To complement ongoing experimental studies developing such pores and measuring signals in response to the presence of DNA, we conducted molecular dynamics simulations of DNA translocation through the nanopore. A typical simulated system included a patch of a silicon nitride membrane dividing water solution of potassium chloride into two compartments connected by the nanopore. External electrical fields induced capturing of the DNA molecules by the pore from the solution and subsequent translocation. Molecular dynamics simulations suggest that 20-basepair segments of double-stranded DNA can transit a nanopore of 2.2 x 2.6 nm(2) cross section in a few microseconds at typical electrical fields. Hydrophobic interactions between DNA bases and the pore surface can slow down translocation of single-stranded DNA and might favor unzipping of double-stranded DNA inside the pore. DNA occluding the pore mouth blocks the electrolytic current through the pore; these current blockades were found to have the same magnitude as the blockade observed when DNA transits the pore. The feasibility of using molecular dynamics simulations to relate the level of the blocked ionic current to the sequence of DNA was investigated.

}, keywords = {Biological Transport, Biophysics, DNA, Electrophoresis, Electrophysiology, Hemolysin Proteins, Ions, Kinetics, Metals, Models, Molecular, Models, Statistical, Nanotechnology, Nucleic Acid Conformation, Oxides, Semiconductors, Stress, Mechanical, Time Factors}, issn = {0006-3495}, doi = {10.1529/biophysj.104.042960}, author = {Aleksei Aksimentiev and Jiunn B Heng and Gregory Timp and Klaus Schulten} } @article {183, title = {Morphology of surfaces in mesoscopic polymers, surfactants, electrons, or reaction-diffusion systems: Methods, simulation and measurements}, journal = {Advances in Chemical Physics}, volume = {121}, year = {2002}, pages = {141{\textendash}239}, abstract = {

In this chapter the authors discuss systems with internal surfaces, ordered surfaces, topological transformations, and dynamical scaling. In Section II the authors show specific examples of mesoscopic systems with special attention devoted to the surfaces in the system{\textemdash}that is, periodic surfaces in surfactant systems, periodic surfaces in diblock copolymers, bicontinuous disordered interfaces in spinodally decomposing blends, ordered charge density wave patterns in electron liquids, and dissipative structures in reaction{\textendash}diffusion systems. Section III covers the theory of morphological measures, including the Euler characteristic and the Gaussian and mean curvatures.

}, doi = {10.1002/0471264318.ch3}, author = {Aleksei Aksimentiev and Robert Ho{\l}yst and Marcin Fialkowski} }