482 research outputs found

    Solvent Effects on Ionization Potentials of Guanine Runs and Chemically Modified Guanine in Duplex DNA: Effect of Electrostatic Interaction and Its Reduction due to Solvent

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    We examined the ionization potential (IP) corresponding to the free energy of a hole on duplex DNA by semiempirical molecular orbital theory with a continuum solvent model. As for the contiguous guanines (a guanine run), we found that the IP in the gas phase significantly decreases with the increasing number of nucleotide pairs of the guanine run, whereas the IP in water (OP, oxidation potential) only slightly does. The latter result is consistent with the experimental result for DNA oligomers in water. This decrease in the IP is mainly due to the attractive electrostatic interaction between the hole and a nucleotide pair in the duplex DNA. This interaction is reduced in water, which results in the small decrease in the IP in water. This mechanism explains the discrepancy between the experimental result and the previous computational results obtained by neglecting the solvent. As for the chemically modified guanine, the previous work showed that the removal of some solvent (water) molecules due to the attachment of a neutral functional group to a guanine in a duplex DNA stabilizes the hole on the guanine. One might naively have expected the opposite case, since a polar solvent usually stabilizes ions. This mechanism also explains this unexpected stabilization of a hole as follows. When some water molecules are removed, the attractive electrostatic interaction stabilizing the hole increases, and thus, the hole is stabilized. In order to design the hole energetics by a chemical modification of DNA, this mechanism has to be taken into account and can be used. 1

    A systematically coarse-grained model for DNA, and its predictions for persistence length, stacking, twist, and chirality

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    We introduce a coarse-grained model of DNA with bases modeled as rigid-body ellipsoids to capture their anisotropic stereochemistry. Interaction potentials are all physicochemical and generated from all-atom simulation/parameterization with minimal phenomenology. Persistence length, degree of stacking, and twist are studied by molecular dynamics simulation as functions of temperature, salt concentration, sequence, interaction potential strength, and local position along the chain, for both single- and double-stranded DNA where appropriate. The model of DNA shows several phase transitions and crossover regimes in addition to dehybridization, including unstacking, untwisting, and collapse which affect mechanical properties such as rigidity and persistence length. The model also exhibits chirality with a stable right-handed and metastable left-handed helix.Comment: 30 pages, 20 figures, Supplementary Material available at http://www.physics.ubc.ca/~steve/publications.htm

    Multiscale model of electronic behavior and localization in stretched dry DNA

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    When the DNA double helix is subjected to external forces it can stretch elastically to elongations reaching 100% of its natural length. These distortions, imposed at the mesoscopic or macroscopic scales, have a dramatic effect on electronic properties at the atomic scale and on electrical transport along DNA. Accordingly, a multiscale approach is necessary to capture the electronic behavior of the stretched DNA helix. To construct such a model, we begin with accurate density-functional-theory calculations for electronic states in DNA bases and base pairs in various relative configurations encountered in the equilibrium and stretched forms. These results are complemented by semi-empirical quantum mechanical calculations for the states of a small size [18 base pair poly(CG)–poly(CG)] dry, neutral DNA sequence, using previously published models for stretched DNA. The calculated electronic states are then used to parametrize an effective tight-binding model that can describe electron hopping in the presence of environmental effects, such as the presence of stray water molecules on the backbone or structural features of the substrate. These effects introduce disorder in the model hamiltonian which leads to electron localization. The localization length is smaller by several orders of magnitude in stretched DNA relative to that in the unstretched structure

    Structural Rigidity of Paranemic (PX) and Juxtapose (JX) DNA Nanostructures

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    Crossover motifs are integral components for designing DNA based nanostructures and nanomechanical devices due to their enhanced rigidity compared to the normal B-DNA. Although the structural rigidity of the double helix B-DNA has been investigated extensively using both experimental and theoretical tools, to date there is no quantitative information about structural rigidity and the mechanical strength of parallel crossover DNA motifs. We have used fully atomistic molecular dynamics simulations in explicit solvent to get the force-extension curve of parallel DNA nanostructures to characterize their mechanical rigidity. In the presence of mono-valent Na+ ions, we find that the stretch modulus (\gamma_1) of the paranemic crossover (PX) and its topo-isomer JX DNA structure is significantly higher (~ 30%) compared to normal B-DNA of the same sequence and length. However, this is in contrast to the original expectation that these motifs are almost twice rigid compared to the double-stranded B-DNA. When the DNA motif is surrounded by a solvent with Mg2+ counterions, we find an enhanced rigidity compared to Na+ environment due to the electrostatic screening effects arising from the divalent nature of Mg2+ ions. This is the first direct determination of the mechanical strength of these crossover motifs which can be useful for the design of suitable DNA for DNA based nanostructures and nanomechanical devices with improved structural rigidity.Comment: 30 pages, 7 figure

    Fluorescence and NMR Studies of the Role of Metal Ions in HIV-1 Genomic RNA Dimerization and Maturation

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    The dimerization initiation site (DIS) is an essential RNA element responsible for dimerization of HIV-1 genomic RNA through a kissing loop interaction. The DIS loop contains six auto-complementary nucleotides stabilized by 5'- and 3'-flanking purines. NCp7 chaperone protein catalyzes conversion of an intermediate DIS kissing dimer to a more thermodynamically stable extended duplex dimer in the presence of Mg2+. Sequence constructs intended to model the extended duplex, (DIS 21), and the kissing dimer, DIS23(GA)*DIS23(HxUC), were designed to examine the structural information and biochemical behaviors during maturation. We introduced the fluorescent labeling, 2-aminopurine (2-AP) into these RNA constructs, to finely probe structural transition and local dynamics accompanied by the formation of the DIS dimer. The 2-AP nucleotides were inserted either in the DIS loop or junction to study loop-loop interaction or purine base stacking conformation at the junction responding to the metal ion effect. High resolution NMR methods were then used to probe structural changes associated with mono versus divalent cation binding to the DIS dimers and also determine the Mg2+ binding sites. Significant chemical shift perturbations (CSP) were found upon Mg2+ binding and used to map structural changes. Further Mn2+ paramagnetic relaxation enhancement (PRE) experiments provided evidence for specific Mg2+ ion binding are localized around the 5' purine bases in both the extended duplex and kissing dimers with profound line broadening effects. Mapping the CSP and PRE data onto the available X-ray crystal and NMR solution structures allowed localization of specific Mg2+ ions at binding sites on the DIS dimers created by the unpaired flanking DIS loop purine nucleotides. Our data indicates that the conformations that are metal cation dependent. These findings are consistent with previous results that suggested a role for divalent metal cations in stabilizing the DIS kissing dimer structure and influencing its maturation to an extended duplex form through interactions with the DIS loop

    DFT study of the electronic structure of neutral, cationic and anionic states of DNA: role of the phosphate backbone.

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    Chan Sze-ki.Thesis submitted in: December 2004.Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.Includes bibliographical references (leaves 73-76).Abstracts in English and Chinese.ABSTRACT (English Version) --- p.iiiABSTRACT (Chinese Version) --- p.ivACKNOWLEDGEMENTS --- p.vTABLE OF CONTENTS --- p.viLIST OF TABLES --- p.viiiLIST OF FIGURES --- p.xiChapter CHAPTER 1 --- INTRODUCTIONChapter 1.1. --- Structure of Deoxyribonucleic acid (DNA)Chapter 1.1.1. --- Configuration and Conformation of Deoxyribonucleic acid (DNA) --- p.1Chapter 1.1.2. --- Torsion Angle --- p.2Chapter 1.1.3. --- Base Pairing --- p.5Chapter 1.2. --- DNA Damage --- p.6Chapter 1.3. --- The Objective of this Project --- p.11Chapter CHAPTER 2 --- theory and Computational DetailsChapter 2.1. --- Computational TheoryChapter 2.1.1. --- Density Functional Theory (DFT) --- p.12Chapter 2.1.2. --- Closed-shell and Open-shell Determinantal Wavefunctions --- p.13Chapter 2.1.3. --- Calculation Method --- p.13Chapter 2.1.4. --- Basis Set Details --- p.14Chapter 2.2. --- Ionization Potential and Electron Affinity --- p.15Chapter 2.3. --- Charge Distribution --- p.16Chapter 2.4. --- Molecular Orbital --- p.16Chapter 2.5. --- Computation Details in this ProjectChapter 2.5.1. --- Calculation Method --- p.17Chapter 2.5.2. --- Studied Model --- p.17Chapter CHPATER 3 --- Results and DiscussionChapter 3.1. --- Neutral StateChapter 3.1.1. --- Bond Length --- p.19Chapter 3.1.2. --- Torsion Angle of DNA backbone --- p.19Chapter 3.1.3. --- Sugar Ring Puckering Mode --- p.25Chapter 3.1.4. --- Natural Population Analysis (NAP) --- p.28Chapter 3.1.5. --- Molecular Orbitals --- p.31Chapter 3.2. --- Cationic StateChapter 3.2.1. --- Ionization Potential --- p.33Chapter 3.2.2. --- Bond Length --- p.34Chapter 3.2.3. --- Backbone Torsion Angles --- p.38Chapter 3.2.4. --- Puckering Mode of Sugar Ring --- p.40Chapter 3.2.5. --- Charge Distribution --- p.43Chapter 3.2.6. --- Molecular Orbitals --- p.43Chapter 3.2.7. --- Summary --- p.47Chapter 3.3. --- Anionic StateChapter 3.3.1. --- Ionization Potential --- p.51Chapter 3.3.2. --- Bond Lengths --- p.52Chapter 3.3.3. --- Torsion Angles of Backbone --- p.54Chapter 3.3.4. --- Sugar Ring Puckering Mode --- p.54Chapter 3.3.5. --- Charge Distribution --- p.58Chapter 3.3.6. --- Molecular Orbital --- p.63Chapter 3.3.7. --- Summary --- p.66Chapter CHAPTER 4 --- CONCLUSION AND FUTURE WORKChapter 4.1. --- Conclusion --- p.68Chapter 4.2. --- Future Work --- p.71REFERENCE --- p.7

    Quantum chemical studies of metal-DNA interactions

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    A series of density functional theory (DFT) and quantum mechanics/molecular mechanics (QM/MM) calculations are used to investigate the binding of platinum and ruthenium anticancer drugs to DNA. The qualitative and quantitative features of Becke's half-and-half (BHandH) functional for calculating geometries, binding energies and harmonic frequencies of non- covalently bound systems are tested and the intermolecular interactions are characterised and quantified using the QTAIM electron densities. Application of this DFT-QTAIM approach to complexes of the type (n6-arene)Ru(en)(nucleobase) 2+ shows a clear preference for binding at guanine over any other base both in gas phase and in aqueous solution, a trend explained on the basis of QTAIM and molecular orbital data. Key parameters of the QM/MM methodology within the ONIOM scheme and efficient geometry optimisation strategies are examined for applications involving DNA oligonucleotides. Calculations on cis- Pt(NH3)2 2+ (cisplatin) bound to d(CpCpTpGpGpTpCpC).(GpGpApCpCpApGpG) reveal that proper consideration of the electrostatics between the QM an MM regions can lead to acceptable geometries, especially when explicit solvent molecules are present. This approach is used to explore the effects of methyl substitution on the binding of a series of Pt(en)2+ (en: ethylenediamine) complexes to dinucleotides. Among the examined methyl derivatives, significant differences are observed for the variants whose en nitrogen atoms are multiply methylated. Binding energies are found to be in excellent correlation with in vitro cytotoxicity data expressed as -log(IC5o). The above mentioned cisplatin-oligonucleotide complex is compared against three clinically approved platinum drugs (carboplatin, heptaplatin and lobaplatin). Calculations on truncated models show a stronger binding for cisplatin among the four complexes and numerous intermolecular interactions are located via QTAIM analysis in the lobaplatin and heptaplatin complexes. Additionally, subtle differences in key geometrical parameters are observed among the complexes around the sites of platination, with the exception of unusually short interplanar base - base distances in the complexes of loba- and heptaplatin. Finally, the same QM/MM methodology is applied to oligonucleotide sequences of five base pairs that contain difluorotoluene or mismatched base pairs, which are shown to be too flexible to be optimised at reliable structures at the chosen level of truncation. Comparisons among obtained structures using different input parameters further validate the followed QM/MM approach

    A Multi-Scale Computational Study on the Mechanism of Streptococcus pneumoniae Nicotinamidase (SpNic)

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    Nicotinamidase (Nic) is a key zinc-dependent enzyme in NAD metabolism that catalyzes the hydrolysis of nicotinamide to give nicotinic acid. A multi-scale computational approach has been used to investigate the catalytic mechanism, substrate binding and roles of active site residues of Nic from Streptococcus pneumoniae (SpNic). In particular, density functional theory (DFT), molecular dynamics (MD) and ONIOM quantum mechanics/molecular mechanics (QM/MM) methods have been employed. The overall mechanism occurs in two stages: (i) formation of a thioester enzyme-intermediate (IC2) and (ii) hydrolysis of the thioester bond to give the products. The polar protein environment has a significant effect in stabilizing reaction intermediates and in particular transition states. As a result, both stages effectively occur in one step with Stage 1, formation of IC2, being rate limiting barrier with a cost of 53.5 kJ•mol−1 with respect to the reactant complex, RC. The effects of dispersion interactions on the overall mechanism were also considered but were generally calculated to have less significant effects with the overall mechanism being unchanged. In addition, the active site lysyl (Lys103) is concluded to likely play a role in stabilizing the thiolate of Cys136 during the reaction
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