Dynamical Form-Factor of Neutron Scattering by DNA Solitons

Method of scattering of slow neutrons has been considered in recent years as a rather perspective way to study the nonlinear DNA dynamics. In this paper we present the results of theoretical calculations of the dynamical form-factor of the scattering. The calculations were made on the basis of the nonlinear mathematical model which takes into account rotational motions of bases around the sugar-phosphate chains. The results of the calculations are considered as predictions for further neutron scattering experiments.     

Influence of dissipation and external field on the dynamics of local deformations in DNA

The dynamics of local deformations in DNA is studied in a simple mathematical model based on the sine-Gordon equation with two additional terms, one accounting for the effects of dissipation and the other for the action of an external field. The energy method is used to derive equations for the velocity of the local deformation as a function of time. Conditions are determined when dissipation and continuous external action are balanced, whereby the deformation can move along the DNA at a constant velocity. The velocity vs. time plots are shown for homopolynucleotide chains at model parameter values: initial velocity v ₀ = 189 m/s, dissipation coefficient \(\overline \beta ^{DNA} \) = 4.25·10^?34 J s, and generalized external force F ₀ ^DNA = = 3.12·10^?22 J. The correspondence of these value with available experimental data is discussed.     

Melting of DNA Oligomers: Dynamical Models and Comparison with Experimental Results

We compare experimental melting curves of short heterogeneous DNA oligomers with theoretical curves derived from statistical mechanics. Partition functions are computed with the one-dimensional Peyrard-Bishop (PB) Hamiltonian, already used in the study of the melting of long DNA chains. Working with short chains we take into account, in the computations, not only the breaking of the interstrand hydrogen bonds, but also the complete dissociation of the double helix into separate single strands. Since this dissociation equilibrium is of general relevance, independent of the particular microscopic model, we give some details of its treatment. We discuss how the non bonded three-dimensional interactions, not explicitly considered in the one-dimensional PB model, are taken into account through the treatment of the dissociation equilibrium. We also evaluate the relevance of the dissociation as a function of the chain length.     

Coupling dynamic models of climate and vegetation

Numerous studies have underscored the importance of terrestrial ecosystems as an integral component of the Earth's climate system. This realization has already led to efforts to link simple equilibrium vegetation models with Atmospheric General Circulation Models through iterative coupling procedures. While these linked models have pointed to several possible climate–vegetation feedback mechanisms, they have been limited by two shortcomings: (i) they only consider the equilibrium response of vegetation to shifting climatic conditions and therefore cannot be used to explore transient interactions between climate and vegetation; and (ii) the representations of vegetation processes and land-atmosphere exchange processes are still treated by two separate models and, as a result, may contain physical or ecological inconsistencies. Here we present, as a proof concept, a more tightly integrated framework for simulating global climate and vegetation interactions. The prototype coupled model consists of the GENESIS (version 2) Atmospheric General Circulation Model and the IBIS (version 1) Dynamic Global Vegetation Model. The two models are directly coupled through a common treatment of land surface and ecophysiological processes, which is used to calculate the energy, water, carbon, and momentum fluxes between vegetation, soils, and the atmosphere. On one side of the interface, GENESIS simulates the physics and general circulation of the atmosphere. On the other side, IBIS predicts transient changes in the vegetation structure through changes in the carbon balance and competition among plants within terrestrial ecosystems. As an initial test of this modelling framework, we perform a 30 year simulation in which the coupled model is supplied with modern CO₂ concentrations, observed ocean temperatures, and modern insolation. In this exploratory study, we run the GENESIS atmospheric model at relatively coarse horizontal resolution (4.5° latitude by 7.5° longitude) and IBIS at moderate resolution (2° latitude by 2° longitude). We initialize the models with globally uniform climatic conditions and the modern distribution of potential vegetation cover. While the simulation does not fully reach equilibrium by the end of the run, several general features of the coupled model behaviour emerge. We compare the results of the coupled model against the observed patterns of modern climate. The model correctly simulates the basic zonal distribution of temperature and precipitation, but several important regional biases remain. In particular, there is a significant warm bias in the high northern latitudes, and cooler than observed conditions over the Himalayas, central South America, and north-central Africa. In terms of precipitation, the model simulates drier than observed conditions in much of South America, equatorial Africa and Indonesia, with wetter than observed conditions in northern Africa and China. Comparing the model results against observed patterns of vegetation cover shows that the general placement of forests and grasslands is roughly captured by the model. In addition, the model simulates a roughly correct separation of evergreen and deciduous forests in the tropical, temperate and boreal zones. However, the general patterns of global vegetation cover are only approximately correct: there are still significant regional biases in the simulation. In particular, forest cover is not simulated correctly in large portions of central Canada and southern South America, and grasslands extend too far into northern Africa. These preliminary results demonstrate the feasibility of coupling climate models with fully dynamic representations of the terrestrial biosphere. Continued development of fully coupled climate-vegetation models will facilitate the exploration of a broad range of global change issues, including the potential role of vegetation feedbacks within the climate system, and the impact of climate variability and transient climate change on the terrestrial biosphere.     

On the importance of van der Waals interaction in the groove binding of DNA with ligands: restrained molecular dynamics study

Comparison of interaction energy between an oligonucleotide and a DNA-binding ligand in the minor and major groove modes was made by use of restrained molecular dynamics. Distortion in DNA was found for the major groove mode whereas less significant changes for both ligand and DNA were detected for the minor groove binding after molecular dynamics simulation. The conformation of the ligand obtained from the major groove mode resembles that computed with the ligand soaked in water. The van der Waals contact energy was found to be as significant as electrostatic energy and more important for difference in binding energy between these two binding modes. The importance of van der Waals force in groove binding was supported by computations on the complex formed by the repressor peptide fragment from the bacteriophage 434 and its operator oligonucleotide.     

On the thermal stability of DNA in solution of mixed solvents

The study of the changes in UV absorbance of DNA solutions in water/dioxane and water/ethylene glycol mixture at different concentrations shows that the thermal denaturation of DNA is sensitive to the electrical permittivity of the media and the water content. At relative low concentrations of co-solvent the dominant feature is the electrical permittivity. When water content is lower than a critical value, the electrical permittivity is no longer the determinant of the denaturation temperature but the partial volume fraction of water. The critical water content is about 0.69 partial volume fraction of water.     

Biophysical aspects and biological implications of the interaction of benzophenanthridine alkaloids with DNA

Benzophenanthridine alkaloids represent a very interesting and significant group of natural products that exhibit a broad range of biological and pharmacological properties. Among this group of alkaloids, sanguinarine, nitidine, fagaronine, and chelerythrine have the potential to form molecular complexes with DNA structures and have attracted recent attention for their possible clinical and pharmacological utility. This review focuses on the interaction of these alkaloids with polymorphic DNA structures (B-form, Z-form, H^L-form, and triple helical form) reported by several research groups employing various physical techniques such as spectrophotometry, spectrofluorimetry, circular dichroism, NMR spectroscopy, thermal melting, viscometry as well as thermodynamic analysis by isothermal titration calorimetry and differential scanning calorimetry to elucidate the mode and mechanism of action at the molecular level to determine the structure-activity relationship. DNA binding properties of these alkaloids are interpreted in relation to their biological activity.     

Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation

We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule's dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.     

Understanding the structural and dynamic consequences of DNA epigenetic modifications: Computational insights into cytosine methylation and hydroxymethylation

We report a series of molecular dynamics (MD) simulations of up to a microsecond combined simulation time designed to probe epigenetically modified DNA sequences. More specifically, by monitoring the effects of methylation and hydroxymethylation of cytosine in different DNA sequences, we show, for the first time, that DNA epigenetic modifications change the molecule''s dynamical landscape, increasing the propensity of DNA toward different values of twist and/or roll/tilt angles (in relation to the unmodified DNA) at the modification sites. Moreover, both the extent and position of different modifications have significant effects on the amount of structural variation observed. We propose that these conformational differences, which are dependent on the sequence environment, can provide specificity for protein binding.     

Extension of the SAEM algorithm for nonlinear mixed models with 2 levels of random effects

This article focuses on parameter estimation of multilevel nonlinearmixed-effects models (MNLMEMs). These models are used to analyzedata presenting multiple hierarchical levels of grouping (clusterdata, clinical trials with several observation periods, ...).The variability of the individual parameters of the regressionfunction is thus decomposed as a between-subject variabilityand higher levels of variability (e.g. within-subject variability).We propose maximum likelihood estimates of parameters of thoseMNLMEMs with 2 levels of random effects, using an extensionof the stochastic approximation version of expectation–maximization(SAEM)–Monte Carlo Markov chain algorithm. The extendedSAEM algorithm is split into an explicit direct expectation–maximization(EM) algorithm and a stochastic EM part. Compared to the originalalgorithm, additional sufficient statistics have to be approximatedby relying on the conditional distribution of the second levelof random effects. This estimation method is evaluated on pharmacokineticcrossover simulated trials, mimicking theophylline concentrationdata. Results obtained on those data sets with either the SAEMalgorithm or the first-order conditional estimates (FOCE) algorithm(implemented in the nlme function of R software) are compared:biases and root mean square errors of almost all the SAEM estimatesare smaller than the FOCE ones. Finally, we apply the extendedSAEM algorithm to analyze the pharmacokinetic interaction oftenofovir on atazanavir, a novel protease inhibitor, from theAgence Nationale de Recherche sur le Sida 107-Puzzle 2 study.A significant decrease of the area under the curve of atazanaviris found in patients receiving both treatments.     

Cooperative stabilization of Zn2+:DNA complexes through netropsin binding in the minor groove of FdU-substituted DNA

The simultaneous binding of netropsin in the minor groove and Zn²⁺ in the major groove of a DNA hairpin that includes 10 consecutive FdU nucleotides at the 3′-terminus (3′FdU) was demonstrated based upon NMR spectroscopy, circular dichroism (CD), and computational modeling studies. The resulting Zn²⁺/netropsin: 3′FdU complex had very high thermal stability with aspects of the complex intact at 85?°C, conditions that result in complete dissociation of Mg²⁺ complexes. CD and ¹⁹F NMR spectroscopy were consistent with Zn²⁺ binding in the major groove of the DNA duplex and utilizing F5 and O4 of consecutive FdU nucleotides as ligands with FdU nucleotides hemi-deprotonated in the complex. Netropsin is bound in the minor groove of the DNA duplex based upon 2D NOESY data demonstrating contacts between AH2 ¹H and netropsin ¹H resonances. The Zn²⁺/netropsin: 3′FdU complex displayed increased cytotoxicity towards PC3 prostate cancer (PCa) cells relative to the constituent components or separate complexes (e.g. Zn²⁺:3′FdU) indicating that this new structural motif may be therapeutically useful for PCa treatment.

An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:32     

Unusual dimeric Zn(II)-cytosine complexes: new models of the interaction of Zn(II) with DNA and RNA

Synthesis and crystal structure of two Zn(II) dimer complexes with 1-methylcytosine (1-MeC) are reported. In complex [Zn(2)Cl(4)(mu-1-MeC-O2,N3)(2)] (1), two 1-MeC ligands are bridging two ZnCl(2) moieties. In [Zn(2)(1-MeC-N3)(4)(mu-SO(4))(2)].2H(2)O (2), the sulfates act as bridging ligands and 1-MeC are linked via N3 to Zn(II) as terminal ligands. Both complexes represent the first examples of Zn(II)-pyrimidine dimers. The potential biological significance of 1 and 2 is discussed.     

Electrochemical biosensor evaluation of the interaction between DNA and metallo-drugs

Electrochemical techniques were used to study the interaction between a panel of antiproliferative metallo-drugs and double-stranded DNA immobilized on screen-printed electrodes as a model of the analogous interaction occurring in solution. The propensity of a given metal drug to interact with DNA was measured as a function of the decrease of guanine oxidation signal, which was detected by square wave voltammetry. Estimates of variations in experimental parameters, such as the concentration of complexes, time following dissolution (ageing time) and the presence of chloride, are provided. Presented at the IV Symposium on Pharmaco-Bio- Metallics, October, 29–31, 2004, Lecce (Italy)     

Structure and conformational dynamics of base excision repair DNA glycosylases

DNA glycosylases play a key role in DNA repair, which maintains the integrity of the cell genome. The structures of many DNA glycosylases have been solved to date. The review considers these structures and the dynamics of DNA glycosylase interactions with DNA. The available data suggest that lesion recognition by DNA glycosylases is a highly dynamic process that is accompanied by multiple conformational changes in the enzyme and DNA substrate.     

Tuberculosis models with fast and slow dynamics: the role of close and casual contacts

Models that incorporate local and individual interactions are introduced in the context of the transmission dynamics of tuberculosis (TB). The multi-level contact structure implicitly assumes that individuals are at risk of infection from close contacts in generalized household (clusters) as well as from casual (random) contacts in the general population. Epidemiological time scales are used to reduce the dimensionality of the model and singular perturbation methods are used to corroborate the results of time-scale approximations. The concept and impact of optimal average cluster or generalized household size on TB dynamics is discussed. We also discuss the potential impact of our results on the spread of TB.     

DFT: a dynamic study of the interaction of ethanol and methanol with platinum

The interaction between alcohol molecules and platinum (Pt) was studied using molecular dynamics (MD; Born-Oppenheimer method). Alcohol molecules like ethanol and methanol present a similar molecular structure, with a methyl group (CH₃) at one end and a fragment of hydroxyl (OH) at the other. This fact generates two orientations that are considered in the interaction with Pt. The MD calculation results for these two orientations indicate a preferential orientation due to energy interactions. A plausible reaction mechanism that takes into account the interaction between Pt and alcohol is presented. The charge transference obtained from the Pt–alcohol interaction was also analyzed. The energy for the two orientations was calculated by indicating the preferential orientation. The methyl and hydroxyl groups are involved in heterolytic breakage of hydrogen bonds, joined to a carbon atom in the former and to an oxygen atom in the latter; however, the methyl group reaction seems to be the most important.