Showing papers on "Molecular models of DNA published in 2012"

Sequence-dependent thermodynamics of a coarse-grained DNA model

Abstract: We introduce a sequence-dependent parametrization for a coarse-grained DNA model [T. E. Ouldridge, A. A. Louis, and J. P. K. Doye, J. Chem. Phys. 134, 085101 (2011)] originally designed to reproduce the properties of DNA molecules with average sequences. The new parametrization introduces sequence-dependent stacking and base-pairing interaction strengths chosen to reproduce the melting temperatures of short duplexes. By developing a histogram reweighting technique, we are able to fit our parameters to the melting temperatures of thousands of sequences. To demonstrate the flexibility of the model, we study the effects of sequence on: (a) the heterogeneous stacking transition of single strands, (b) the tendency of a duplex to fray at its melting point, (c) the effects of stacking strength in the loop on the melting temperature of hairpins, (d) the force-extension properties of single strands, and (e) the structure of a kissing-loop complex. Where possible, we compare our results with experimental data and find a good agreement. A simulation code called oxDNA, implementing our model, is available as a free software.

Sequence-dependent thermodynamics of a coarse-grained DNA model

Abstract: We introduce a sequence-dependent parametrization for a coarse-grained DNA model [T. E. Ouldridge, A. A. Louis, and J. P. K. Doye, J. Chem. Phys. 134, 085101 (2011)] originally designed to reproduce the properties of DNA molecules with average sequences. The new parametrization introduces sequence-dependent stacking and base-pairing interaction strengths chosen to reproduce the melting temperatures of short duplexes. By developing a histogram reweighting technique, we are able to fit our parameters to the melting temperatures of thousands of sequences. To demonstrate the flexibility of the model, we study the effects of sequence on: (a) the heterogeneous stacking transition of single strands, (b) the tendency of a duplex to fray at its melting point, (c) the effects of stacking strength in the loop on the melting temperature of hairpins, (d) the force-extension properties of single strands and (e) the structure of a kissing-loop complex. Where possible we compare our results with experimental data and find a good agreement. A simulation code called oxDNA, implementing our model, is available as free software.

Torque measurements reveal sequence-specific cooperative transitions in supercoiled DNA

Abstract: B-DNA becomes unstable under superhelical stress and is able to adopt a wide range of alternative conformations including strand-separated DNA and Z-DNA. Localized sequence-dependent structural transitions are important for the regulation of biological processes such as DNA replication and transcription. To directly probe the effect of sequence on structural transitions driven by torque, we have measured the torsional response of a panel of DNA sequences using single molecule assays that employ nanosphere rotational probes to achieve high torque resolution. The responses of Z-forming d(pGpC)n sequences match our predictions based on a theoretical treatment of cooperative transitions in helical polymers. “Bubble” templates containing 50–100 bp mismatch regions show cooperative structural transitions similar to B-DNA, although less torque is required to disrupt strand–strand interactions. Our mechanical measurements, including direct characterization of the torsional rigidity of strand-separated DNA, establish a framework for quantitative predictions of the complex torsional response of arbitrary sequences in their biological context.

Self-assembly of short DNA duplexes: from a coarse-grained model to experiments through a theoretical link

Abstract: Short blunt-ended DNA duplexes comprising 6 to 20 base pairs self-assemble into polydisperse semiflexible chains due to hydrophobic stacking interactions between terminal base pairs. Above a critical concentration, which depends on temperature and duplex length, such chains order into liquid crystal phases. Here, we investigate the self-assembly of such double-helical duplexes with a combined numerical and theoretical approach. We simulate the bulk system employing the coarse-grained DNA model recently proposed by Ouldridge et al. [J. Chem. Phys., 2011, 134, 08501]. Then we evaluate the input quantities for the theoretical framework directly from the DNA model. The resulting parameterfree theoretical predictions provide an accurate description of the simulation results in the isotropic phase and theoretical values for the isotropic‐nematic phase boundaries which are in line with experimental findings. In addition, the developed theoretical framework makes it possible to provide a route to estimate the stacking free energy.

Solution, surface, and single molecule platforms for the study of DNA-mediated charge transport

Abstract: The structural core of DNA, a continuous stack of aromatic heterocycles, the base pairs, which extends down the helical axis, gives rise to the fascinating electronic properties of this molecule that is so critical for life. Our laboratory and others have developed diverse experimental platforms to investigate the capacity of DNA to conduct charge, termed DNA-mediated charge transport (DNA CT). Here, we present an overview of DNA CT experiments in solution, on surfaces, and with single molecules that collectively provide a broad and consistent perspective on the essential characteristics of this chemistry. DNA CT can proceed over long molecular distances but is remarkably sensitive to perturbations in base pair stacking. We discuss how this foundation, built with data from diverse platforms, can be used both to inform a mechanistic description of DNA CT and to inspire the next platforms for its study: living organisms and molecular electronics.

Innovations in Biomolecular Modeling and Simulations

Abstract: Volume 1 Beginnings Personal Perspective Fashioning NAMD, a History of Risk and Reward: Klaus Schulten Reminisces Towards Biomolecular Simulations with Explicit Inclusion of Polarizability: Development of a CHARMM Polarizable Force Field based on the Classical Drude Oscillator Model Integral Equation Theory of Biomolecules and Electrolytes Molecular Simulation in the Energy Biosciences Sampling and rates Dynamics Simulations with Trajectory Fragments Computing Reaction Rates in Biomolecular Systems using discrete macrostates Challenges in applying Monte Carlo sampling to biomolecular systems Coarse graining and multiscale models Coarse Grained Protein Models Generalized Multi-Level Coarse-Grained Molecular Simulation and Its Applucation to Myosin-V Movement Top-down Mesoscale Models and Free Energy Calculations of Multivalent Protein-Protein and Protein-Membrane Interactions in Nanocarrier Adhesion and Receptor Trafficking Studying Proteins and Peptides at Material Surfaces Multiscale Design: From Theory to Practice. Volume 2 Atomistic simulations of nucleic acids and nucleic acid complexes Modeling nucleic acid structure and flexibility: from atomic to mesoscopic scale Molecular dynamics and force field based methods for studying quadruplex nucleic acids Opposites attract: Shape and Electrostatic Complementarity in Protein/DNA Complexes Intrinsic motions of DNA polymerases underlie their remarkable specificity and selectivity and suggest a hybrid substrate binding mechanism Molecular Dynamics Structure Prediction of a Novel Protein/DNA Complex: Two HU Proteins with a DNA Four-way Junction Molecular Dynamics Simulations of RNA Molecules The Structure and Folding of Helical Junctions in RNA DNA folding, knotting, sliding and hopping Simulations of DNA Knots and Catenanes Monte Carlo Simulations of Nucleosome Chains to Idenitfy Factors that control DNA Compaction and Access Sliding Dynamics Along DNA: a Molecular Perspective Drug design Structure-based design technology: CONTOUR and its aplication to drug discovery Molecular simulation in computer-aided drug design: algorithms and applications Computer-aided drug discovery: two antiviral drugs for HIV AIDS

Coarse-Grained Modelling of DNA and DNA Self-Assembly

Abstract: In this thesis I present a novel coarse-grained model of deoxyribonucleic acid (DNA). The model represents single-stranded DNA as a chain of rigid nucleotides, and includes potentials to represent chain connectivity, excluded volume, hydrogen-bonding and base stacking interactions. The parameterization of these interactions is justified by comparing the model's representation of a range of physical phenomena to experimental data. In particular, the geometrical structure and elastic moduli of duplex DNA, and the flexibility of single-stranded DNA, are shown to be physically reasonable. Additionally, the thermodynamics of single-stranded stacking, duplex hybridization, hairpin formation and more complex motifs are shown to agree well with experimental data. The model is optimized for capturing the thermodynamic and mechanical changes associated with duplex formation from single strands. Considerable attention is therefore given to ensuring that single-stranded DNA behaves physically, an approach which differs from previous attempts to model DNA. As a result, the model is the first in which an explicit stacking transition is present in single strands, and also the only coarse-grained model to date to capture both hairpin formation within a single strand and duplex formation between strands. The scope of the model is demonstrated by simulating DNA tweezers, an iconic nanodevice -- the first time that coarse-grained modelling has been applied to dynamic DNA nanotechnology. The simulations suggest that branch migration during toehold-mediated strand displacement -- a central feature of many nanomachines -- does not have a flat free-energy profile, as is generally assumed. This finding may help to explain the observed dependence of displacement rate on toehold length. Finally, the operation of a two-footed DNA walker on a single-stranded DNA track is considered. The model suggests that several aspects of the walker will reduce its efficiency, including a tendency to bind to an undesired site on the track. Several design modifications are suggested to improve the operation of the walker.

Simulating a burnt-bridges DNA motor with a coarse-grained DNA model

Abstract: We apply a recently-developed coarse-grained model of DNA, designed to capture the basic physics of nanotechnological DNA systems, to the study of a `burnt-bridges' DNA motor consisting of a single-stranded cargo that steps processively along a track of single-stranded stators. We demonstrate that the model is able to simulate such a system, and investigate the sensitivity of the stepping process to the spatial separation of stators, finding that an increased distance can suppress successful steps due to the build up of unfavourable tension. The mechanism of suppression suggests that varying the distance between stators could be used as a method for improving signal-to-noise ratios for motors that are required to make a decision at a junction of stators.

Effect of structural dynamics and base pair sequence on the nature of excited states in DNA hairpins.

Abstract: In this article, a theoretical study of the electronic and spectroscopic properties of well-defined DNA hairpins is presented. The excited states in the hairpins are described in terms of an exciton Hamiltonan model, and the structural dynamics of the DNA model systems is explicitly taken into account by molecular dynamics simulations. The results show that the model reproduces the experimentally observed absorption and circular dichroism spectra accurately in most cases. It is shown that structural disorder leads to excited states that are largely localized on a single base pair, even for regular DNA sequences consisting only of AT base pairs. Variations in the base pair sequence have a significant effect on the appearance of the spectra but also on the degree of delocalization of the excited state.

Influence of hyperthermophilic protein Cren7 on the stability and conformation of DNA: insights from molecular dynamics simulation and free energy analysis.

Abstract: Cren7, a novel chromatin protein highly conserved among crenarchaea, plays an important role in genome packaging and gene regulation. However, the detail dynamical structural characteristic of the Cren7–DNA complex and the detail study of the DNA in the complex have not been done. Focused on two specific Cren7–DNA complexes (PDB codes 3LWH and 3LWI), we applied molecular dynamics (MD) simulations at four different temperatures (300, 350, 400, and 450 K) and the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) free energy calculation at 300 and 350 K to examine the role of Cren7 protein in enhancing the stability of DNA duplexes via protein–DNA interactions, and to study the structural transition in DNA. The simulation results indicate that Cren7 stabilizes DNA duplex in a certain temperature range in the binary complex compared with the unbound DNA molecules. At the same time, DNA molecules were found to undergo B-like to A-like form transitions with increased temperature. The results of stati...

DNA conformation in nanochannels: Monte Carlo simulation studies using a primitive DNA model.

Abstract: We have performed canonical ensemble Monte Carlo simulations of a primitive DNAmodel to study the conformation of 2.56 ∼ 21.8 μm long DNA molecules confined in nanochannels at various ionic concentrations with the comparison of our previous experimental findings. In the model, the DNA molecule is represented as a chain of charged hard spheres connected by fixed bond length and the nanochannels as planar hard walls. System potentials consist of explicit electrostatic potential along with short-ranged hard-sphere and angle potentials. Our primitive model system provides valuable insight into the DNAconformation, which cannot be easily obtained from experiments or theories. First, the visualization and statistical analysis of DNA molecules in various channel dimensions and ionic strengths verified the formation of locally coiled structures such as backfolding or hairpin and their significance even in highly stretched states. Although the folding events mostly occur within the region of ∼0.5 μm from both chain ends, significant portion of the events still take place in the middle region. Second, our study also showed that two controlling factors such as channel dimension and ionic strength widely used in stretching DNA molecules have different influence on the local DNA structure. Ionic strength changes local correlation between neighboring monomers by controlling the strength of electrostatic interaction (and thus the persistence length of DNA), which leads to more coiled local conformation. On the other hand, channel dimension controls the overall stretch by applying the geometric constraint to the non-local DNAconformation instead of directly affecting local correlation. Third, the molecular weight dependence of DNA stretch was observed especially in low stretch regime, which is mainly due to the fact that low stretch modes observed in short DNA molecules are not readily accessible to much longer DNA molecules, resulting in the increase in the stretch of longer DNA molecules.

3D molecular assembling of B-DNA sequences using nucleotides as building blocks

Abstract: Unlike the current atomistic DNA models, this paper proposes a new 3D space-filling model for sequences of DNA base pairs using nucleotides, instead of atoms, as building blocks of DNA molecules. This nucleotide-based model is more scalable than the traditional atomistic model, and has the advantage that easily adapts to any topological conformation of DNA. Interestingly, this model also allows the building of the molecular surface of the DNA, either partly or entirely, as needed for energy computations in molecular applications. Moreover, it allows us to grasp the DNA shape at different levels of shape composition: atom, nucleotide, and DNA macromolecule as a whole.

DNA Self-Assembly and Computation Studied with a Coarse-grained Dynamic Bonded Model

Abstract: We study DNA self-assembly and DNA computation using a coarse-grained DNA model within the directional dynamic bonding framework {[}C. Svaneborg, Comp. Phys. Comm. 183, 1793 (2012){]}. In our model, a single nucleotide or domain is represented by a single interaction site. Complementary sites can reversibly hybridize and dehybridize during a simulation. This bond dynamics induces a dynamics of the angular and dihedral bonds, that model the collective effects of chemical structure on the hybridization dynamics. We use the DNA model to perform simulations of the self-assembly kinetics of DNA tetrahedra, an icosahedron, as well as strand displacement operations used in DNA computation.

Intrinsic localized modes in nonlinear models inspired by DNA

Abstract: We discuss nonlinear dynamic models for the fluctuational opening of the base pairs in DNA and show that a standard model which is satisfactory for time-independent properties has to be improved to properly describe the time scales of the fluctuations. The existence of an energy barrier for the closing of the base pairs has to be taken into account. This introduces a model which sustains a new class of Intrinsically Localized Modes (ILMs). We investigate their properties numerically, and then consider two simplified versions of the improved DNA model allowing an analytical study of some properties of those ILMs. The models are different because the effective barrier necessary for the existence of this new class of ILMs is obtained either through the on-site potential or through the nonlinear stacking interaction, but they nevertheless sustain similar nonlinear localized excitations. An extension of the usual anti-continuum limit has to be introduced for the analysis, and relies on a continuation of localized equilibria from infinity.

DNA Self-Assembly and Computation Studied with a Coarse-Grained Dynamic Bonded Model

Abstract: We study DNA self-assembly and DNA computation using a coarse-grained DNA model within the directional dynamic bonding framework [C. Svaneborg, Comp. Phys. Comm. 183, 1793 (2012)]. In our model, a single nucleotide or domain is represented by a single interaction site. Complementary sites can reversibly hybridize and dehybridize during a simulation. This bond dynamics induces a dynamics of the angular and dihedral bonds, that model the collective effects of chemical structure on the hybridization dynamics. We use the DNA model to perform simulations of the self-assembly kinetics of DNA tetrahedra, an icosahedron, as well as strand displacement operations used in DNA computation.

Mechanistic insight into the structure and dynamics of entangled and hydrated λ-phage DNA.

Abstract: Intrinsic dynamics of DNA plays a crucial role in DNA protein interactions and has been emphasized as a possible key component for in vivo chromatin organization. We have prepared an entangled DNA microtube above the overlap concentration by exploiting the complementary cohesive ends of lambda-phage DNA, which is confirmed by atomic force microscopy and agarose gel electrophoresis. Photon correlation spectroscopy further confirmed that the entangled solutions are found to exhibit the classical hydrodynamics of a single chain segment on length scales smaller than the hydrodynamic length scale of single lambda-phage DNA molecule. We also observed that in 41.6% (gm water/gm DNA) hydrated state, lambda-phage DNA exhibits a dynamic transition temperature (T-dt) at 187 K and a crossover temperature (T-c) at 246 K. Computational insight reveals that the observed structure and dynamics of entangled lambda-phage DNA are distinctively different from the behavior of the corresponding unentangled DNA with open cohesive ends, which is reminiscent with our experimental observation.

Principles of DNA architectonics: design of DNA-based nanoobjects

Abstract: The methods of preparation of monomeric DNA blocks that serve as key building units for the construction of complex DNA objects are described Examples are given of the formation of DNA blocks based on native and modified oligonucleotide components using hydrogen bonding and nucleic acid-specific types of bonding and also some affinity interactions with RNA, proteins, ligands The static discrete and periodic two- and three-dimensional DNA objects reported to date are described systematically Methods used to prove the structures of DNA objects and the prospects for practical application of nanostructures based on DNA and its analogues in biology, medicine and biophysics are considered The bibliography includes 195 references

Insights into the thermal stabilization and conformational transitions of DNA by hyperthermophile protein Sso7d: molecular dynamics simulations and MM-PBSA analysis

Abstract: In the assembly of DNA-protein complex, the DNA kinking plays an important role in nucleoprotein structures and gene regulation. Molecular dynamics (MD) simulations were performed on specific protein-DNA complexes in this study to investigate the stability and structural transitions of DNA depending on temperature. Furthermore, we introduced the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) approach to analyze the interactions between DNA and protein in hyperthermophile. Focused on two specific Sso7d-DNA complexes (PDB codes: 1BNZ and 1BF4), we performed MD simulations at four temperatures (300, 360, 420, and 480 K) and MM-PBSA at 300 and 360 K to illustrate detailed information on the changes of DNA. Our results show that Sso7d stabilizes DNA duplex over a certain temperature range and DNA molecules undergo B-like to A-like form transitions in the binary complex with the temperature increasing, which are consistent with the experimental data. Our work will contribute to a better understanding of protein-DNA interaction.

Non-Ideality of a DNA Strand Displacement AND Gate Studied with a Dynamic Bonded DNA Model

Abstract: We perform a spatially resolved simulation study of an AND gate based on DNA strand displacement using several lengths of the toehold and the adjacent domains. DNA strands are modelled using a coarse-grained dynamic bonding model {[}C. Svaneborg, Comp. Phys. Comm. 183, 1793 (2012){]}. We observe a complex transition path from the initial state to the final state of the AND gate. This path is strongly influenced by non-ideal effects due to transient bubbles revealing undesired toeholds and thermal melting of whole strands. We have also characterized the bound and unbound kinetics of single strands, and in particular the kinetics of the total AND operation and the three distinct distinct DNA transitions that it is based on. We observe a exponential kinetic dependence on the toehold length of the competitive displacement operation, but that the gate operation time is only weakly dependent on both the toehold and adjacent domain length. Our gate displays excellent logical fidelity in three input states, and quite poor fidelity in the fourth input state. This illustrates how non-ideality can have very selective effects on fidelity. Simulations and detailed analysis such as those presented here provide molecular insights into strand displacement computation, that can be also be expected in chemical implementations.

Pair-wise Key Pre-distribution Scheme Based on Extended DNA Model

Abstract: A DNA model based pair-wise key establishment scheme is analyzed and the result shows that the resilience of the scheme is poorCombining DNA model with the idea of multiple key pool,an extended DNA model based pair-wise key establishment scheme is proposedThe gray degree of the variable is changed form 2 toThe nodes select multi-DNA strands as its key ring and use the code of some oligonucleotide in some DNA strand as their actual pair-wise keyThe key connectivity,security and overhead of the scheme are discussedThe analysis shows that the overhead of computation and communication of the new scheme is little and the security is greatly improved compared with the original DNA model scheme

Electronic localization at mesoscopic length scales: different definitions of localization and contact effects in a heuristic DNA model

Abstract: In this work we investigate the electronic transport along model DNA molecules using an effective tight-binding approach that includes the backbone on site energies. The localization length and participation number are examined as a function of system size, energy dependence, and the contact coupling between the leads and the DNA molecule. On one hand, the transition from an diffusive regime to a localized regime for short systems is identified, suggesting the necessity of a further length scale revealing the system borders sensibility. On the other hand, we show that the lenght localization and participation number, do not depended of system size and contact coupling in the thermodynamic limit. Finally we discuss possible length dependent origins for the large discrepancies among experimental results for the electronic transport in DNA sample.

Self-assembly of short DNA duplexes: from a coarse-grained model to experiments through a theoretical link

Abstract: Short blunt-ended DNA duplexes comprising 6 to 20 base pairs self-assemble into polydisperse semi-flexible chains due to hydrophobic stacking interactions between terminal base pairs. Above a critical concentration, which depends on temperature and duplex length, such chains order into liquid crystal phases. Here, we investigate the self-assembly of such double-helical duplexes with a combined numerical and theoretical approach. We simulate the bulk system employing the coarse-grained DNA model recently proposed by Ouldridge et al. [ J. Chem. Phys. 134, 08501 (2011) ]. Then we evaluate the input quantities for the theoretical framework directly from the DNA model. The resulting parameter-free theoretical predictions provide an accurate description of the simulation results in the isotropic phase. In addition, the theoretical isotropic-nematic phase boundaries are in line with experimental findings, providing a route to estimate the stacking free energy.

A Novel DNA Model

Abstract: When this project was started in 2007, very few models were available in the literature. In particular, no thermodynamic simulations of systems involving branched duplexes had been performed. It was therefore necessary to establish whether the aim of simulating nanotechnology with a coarse-grained model was a feasible one.