Biomedical subjects

Lars Nordenskiöld

Publications and source records attributed to Lars Nordenskiöld.

14 recordsLinked to original sources

PubMed2006

Charge structure and counterion distribution in hexagonal DNA liquid crystal.

A hexagonal liquid crystal of DNA fragments (double-stranded, 150 basepairs) with tetramethylammonium (TMA) counterions was investigated with small angle neutron scattering (SANS). We obtained the structure factors pertaining to the DNA and counterion density correlations with contrast matching in the water. Molecular dynamics (MD) computer simulation of a hexagonal assembly of nine DNA molecules showed that the inter-DNA distance fluctuates with a correlation time around 2 ns and a standard deviation of 8.5% of the interaxial spacing. The MD simulation also showed a minimal effect of the fluctuations in inter-DNA distance on the radial counterion density profile and significant penetration of the grooves by TMA. The radial density profile of the counterions was also obtained from a Monte Carlo (MC) computer simulation of a hexagonal array of charged rods with fixed interaxial spacing. Strong ordering of the counterions between the DNA molecules and the absence of charge fluctuations at longer wavelengths was shown by the SANS number and charge structure factors. The DNA-counterion and counterion structure factors are interpreted with the correlation functions derived from the Poisson-Boltzmann equation, MD, and MC simulation. Best agreement is observed between the experimental structure factors and the prediction based on the Poisson-Boltzmann equation and/or MC simulation. The SANS results show that TMA is too large to penetrate the grooves to a significant extent, in contrast to what is shown by MD simulation.

Computer Simulation↗

PubMed2006

Computer modeling demonstrates that electrostatic attraction of nucleosomal DNA is mediated by histone tails.

We conducted molecular dynamics computer simulations of charged histone tail-DNA interactions in systems mimicking nucleosome core particles (NCP) . In a coarse-grained model, the NCP is modeled as a negatively charged spherical particle with flexible polycationic histone tails attached to it in a dielectric continuum with explicit mobile counterions and added salt. The size, charge, and distribution of the tails relative to the core were built to mimick real NCP. In this way, we incorporate attractive ion-ion correlation effects due to fluctuations in the ion cloud and the attractive entropic and energetic tail-bridging effects. In agreement with experimental data, increase of monovalent salt content from salt-free to physiological concentration leads to the formation of NCP aggregates; likewise, in the presence of MgCl2, the NCPs form condensed systems via histone-tail bridging and accumulation of counterions. More detailed mechanisms of the histone tail-DNA interactions and dynamics have been obtained from all-atom molecular dynamics simulations (including water), comprising three DNA 22-mers and 14 short fragments of the H4 histone tail (amino acids 5-12) carrying three positive charges on lysine+ interacting with DNA. We found correlation of the DNA-DNA distance with the presence and association of the histone tail between the DNA molecules.

Binding Sites↗

PubMed2006

Folding, misfolding, and amyloid protofibril formation of WW domain FBP28.

We study the folding mechanism of a triple beta-strand WW domain from the Formin binding protein 28 (FBP28) at atomic resolution with explicit water model using replica exchange molecular dynamics computer simulations. Extended sampling over a wide range of temperatures to obtain the free energy, enthalpy, and entropy surfaces as a function of structural coordinates has been performed. Simulations were started from different configurations covering the folded and unfolded states. In the free energy landscape a transition state is identified and its structures and -values are compared with experimental data from a homologous protein, the prolyl-isomerase Pin1 WW domain. A stable intermediate state is found to accumulate during the simulation characterized by the carboxyl-terminal beta-strand 3 having misregistered hydrogen bonds and where the structural heterogeneity is due to nonnative turn II formation. Furthermore, the aggregation behavior of the FBP28 WW domain may be related to one such misfolded structure, which has a much lower free energy of dimer formation than that of the native dimer. Based on the misfolded dimer, aggregation to form protofibril structure is discussed.

Amyloid↗

PubMed2006

Similarities and differences in interaction of K+ and Na+ with condensed ordered DNA. A molecular dynamics computer simulation study.

Four 20 ns molecular dynamics simulations have been performed with two counterions, K+ or Na+, at two water contents, 15 or 20 H2O per nucleotide. A hexagonal simulation cell comprised of three identical DNA decamers [d(5'-ATGCAGTCAG) x d(5'-TGACTGCATC)] with periodic boundary condition along the DNA helix was used. The simulation setup mimics the DNA state in oriented DNA fibers or in crystals of DNA oligomers. Variation of counterion nature and water content do not alter averaged DNA structure. K+ and Na+ binding to DNA are different. K+ binds to the electronegative sites of DNA bases in the major and the minor grooves, while Na+ interacts preferentially with the phosphate groups. Increase of water causes a shift of both K+ and Na+ from the first hydration shell of O1P/O2P and of the DNA bases in the minor groove with lesser influence for the cation binding to the bases in the major groove. Mobility of both water and cations in the K-DNA systems is faster than in the Na-DNA systems: Na+ organizes and immobilizes water structure around itself and near DNA while for K+ water is less organized and more dynamic.

Base Pairing↗

PubMed2005

Electrical conduction in macroscopically oriented deoxyribonucleic and hyaluronic acid samples.

Measurements of the quasistatic and frequency dependent electrical conductivity below 1 MHz were carried out on wet-spun, macroscopically oriented, calf thymus deoxyribonucleic (DNA) and umbilical cord hyaluronic acid (HA) bulk samples. The frequency dependence of the electrical conductivity in the frequency range of approximately 10(-3) - 10(6) Hz of both materials is surprisingly rather similar. Temperature dependence of the quasistatic electrical conductivity above the low temperature saturation plateau can be well described by the activated Arrhenius law with the activation energy of approximately 0.8 eV for both DNA and HA. We discuss the meaning of these findings for the possible conduction mechanism in these particular charged polyelectrolytes.

Complex Mixtures↗

PubMed2004

A molecular dynamics simulation study of polyamine- and sodium-DNA. Interplay between polyamine binding and DNA structure.

Four different molecular dynamics (MD) simulations have been performed for infinitely long ordered DNA molecules with different counterions, namely the two natural polyamines spermidine(3+) (Spd3+) and putrescine(2+) (Put2+), the synthetic polyamine diaminopropane(2+) (DAP2+), and the simple monovalent cation Na+. All systems comprised a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charge. The simulation setup mimics the DNA state in oriented DNA fibers, previously studied using NMR and other experimental methods. In this paper the interplay between polyamine binding and local DNA structure is analyzed by investigating how and if the minor groove width of DNA depends on the presence and dynamics of the counterions. The results of the MD simulations reveal principal differences in the polyamine-DNA interactions between the natural [spermine(4+), Spd3+, Put2+] and the synthetic (DAP2+) polyamines.

Base Sequence↗

PubMed2004

Molecular dynamics simulation study of oriented polyamine- and Na-DNA: sequence specific interactions and effects on DNA structure.

Molecular dynamics (MD) computer simulations have been carried out on four systems that correspond to an infinite array of parallel ordered B-DNA, mimicking the state in oriented DNA fibers and also being relevant for crystals of B-DNA oligonucleotides. The systems were all comprised of a periodical hexagonal cell with three identical DNA decamers, 15 water molecules per nucleotide, and counterions balancing the DNA charges. The sequence of the double helical DNA decamer was d(5'-ATGCAGTCAG)xd(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine(3+) (Spd(3+)) and putrescine(2+) (Put(2+)), the synthetic polyamine diaminopropane(2+) (DAP(2+)), and the simple monovalent cation Na(+). This work compares the specific structures of the polyamine- and Na-DNA systems and how they are affected by counterion interactions. It also describes sequence-specific hydration and interaction of the cations with DNA. The local DNA structure is dependent on the nature of the counterion. Even the very similar polyamines, Put(2+) and DAP(2+), show clear differences in binding to DNA and in effect on hydration and local structure. Generally, the polyamines disorder the hydration of the DNA around their binding sites whereas Na(+) being bound to DNA attracts and organizes water in its vicinity. Cation binding at the selected sites in the minor and in the major groove is compared for the different polyamines and Na(+). We conclude that the synthetic polyamine (DAP(2+)) binds specifically to several structural and sequence-specific motifs on B-DNA, unlike the natural polyamines, Spd(3+) and Put(2+). This specificity of DAP(2+) compared to the more dynamic behavior of Spd(3+) and Put(2+) may explain why the latter polyamines are naturally occurring in cells.

Base Sequence↗

PubMed2003

A molecular dynamics simulation study of oriented DNA with polyamine and sodium counterions: diffusion and averaged binding of water and cations.

Four different molecular dynamics (MD) simulations have been performed for ordered DNA decamers, d(5'-ATGCAGTCAG)*d(5'-TGACTGCATC). The counterions were the two natural polyamines spermidine3+ (Spd3+) and putrescine2+ (Put2+), the synthetic polyamine diaminopropane2+ (DAP2+) and Na+. The simulation set-up corresponds to an infinite array of parallel DNA mimicking the state in oriented DNA fibers or crystals. This work describes general properties of polyamine and Na+ binding to DNA. Simulated diffusion coefficients show satisfactory agreement with experimental NMR diffusion data of comparable systems. The interaction of the polyamines with DNA is dynamic in character and the cations mostly form short-lived contacts with the electronegative binding sites of DNA. Polyamines, Na+ and water interact most frequently with the charged phosphate atoms with preference for association from the minor groove side with O1P over O2P. There is a strong anti-correlation in the cation binding to the electronegative groups of DNA, i.e. the presence of a cation near one of the DNA sites repels other cations from binding to this and to the other sites separated by <7.5 A from each other. In contrast to the other polyamines, DAP2+ is able to form 'bridges' connecting neighboring phosphate groups along the DNA strand. A small fraction of DAP2+ and Put2+ can be found in the major grooves, while Spd3+ is absent there. The results of the MD simulations reveal principal differences in the polyamine-DNA interactions between the natural (Spd3+, Put2+ and spermine4+) and synthetic (DAP2+) polyamines.

Binding Sites↗

PubMed2003

Application of the Poisson Boltzmann polyelectrolyte model for analysis of thermal denaturation of DNA in the presence of Na+ and polyamine cations.

The Poisson Boltzmann (PB) cell model of polyelectrolyte solution has been used for calculation of the electrostatic free energy difference, Delta G(el), between double- and single-stranded DNA. The calculations have been performed for conditions relevant to describe the DNA helix-coil transition in NaCl solution in the presence of the natural polyamines putrescine(2+), spermidine(3+), spermine(4+) and their synthetic homologs with different spacing between the charged amino groups, for which experimental values of the DNA 'melting' transition temperature (T(m)) are available. Using the PB theory and the polyamine ion radius as an adjusting parameter provides quantitative agreement between experimental and theoretical T(m)--salt concentration dependencies only by using physically unreasonable radii for the polyamine. Thus, modeling the linear and flexible polyamines as charged spheres within the PB cell model is an implausible oversimplification. We propose another explanation for the experimental observations, still within the frame of the 'primitive' PB polyelectrolyte theory. This explanation is based on an analysis of the Delta G(el) dependence on the stoichiometry of polyamine-polyanion binding to double- and single-stranded DNA.

Cations↗

PubMed2003

Electrical conduction in native deoxyribonucleic acid: hole hopping transfer mechanism?

Measurements of the quasistatic and frequency dependent electric conductivity below 1 MHz were carried out on wet-spun, macroscopically oriented, calf thymus DNA bulk samples, thus effectively extending previous radio frequency data down to quasistatic time scales. The frequency dependence of the electrical conductivity in the frequency range of approximately 10(-3)-10(15) Hz agrees well with predictions of the hopping hole mechanism. Temperature dependence of the quasistatic electrical conductivity can be rather well described by the activated Arrhenius law with the activation energy of approximately 0.9 eV; however, based on the quality of the fits, the hopping ansatz cannot be ruled out.

Animals↗

PubMed2002

Polyamine-nucleic acid interactions and the effects on structure in oriented DNA fibers.

Fibrous oriented calf thymus DNA containing the natural polyamines spermidine (Spd) and putrescine (Put), and the degradation polyamines cadaverine (Cad) and 1,3-diaminopropane (DAP), have been investigated at different water contents using nuclear magnetic resonance (NMR) methods, fiber X-ray diffraction and gravimetric measurements. When judged by X-ray only the DAP and Spd samples seem to undergo a B-A-form transition at reduced water activity. Solid-state two-dimensional rotor-synchronized magic angle spinning (2D-syncMAS) 31P-NMR, however, shows the A-form to be present also in the Put sample, and it appears that the separation between the amine units of diamines is correlated with the amount of A-form present. In addition, the solid-state NMR data show the polyamine-bound DNA samples to have a significant deviation from the ordinary B-form DNA structure, displaying similar amounts of BI and BII nucleotide conformations. The low water content of the samples suggest that the polyamines themselves act as hydrators of DNA. Water 2H-NMR results are in agreement with this observation. The quadrupolar splittings of the polyamine 2H signals for samples at low water content indicate some preferential spatial orientations of the polyamines in the ordered DNA environment. The polyamines show relatively fast macroscopic diffusion as detected by NMR self-diffusion measurements.

Animals↗

PubMed2002

Metal ion-induced lateral aggregation of filamentous viruses fd and M13.

We report a detailed comparison between calculations of inter-filament interactions based on Monte-Carlo simulations and experimental features of lateral aggregation of bacteriophages fd and M13 induced by a number of divalent metal ions. The general findings are consistent with the polyelectrolyte nature of the virus filaments and confirm that the solution electrostatics account for most of the experimental features observed. One particularly interesting discovery is resolubilization for bundles of either fd or M13 viruses when the concentration of the bundle-inducing metal ion Mg(2+) or Ca(2+) is increased to large (>100 mM) values. In the range of Mg(2+) or Ca(2+) concentrations where large bundles of the virus filaments are formed, the optimal attractive interaction energy between the virus filaments is estimated to be on the order of 0.01 kT per net charge on the virus surface when a recent analytical prediction to the experimentally defined conditions of resolubilization is applied. We also observed qualitatively distinct behavior between the alkali-earth metal ions and the divalent transition metal ions in their action on the charged viruses. The understanding of metal ions-induced reversible aggregation based on solution electrostatics may lead to potential applications in molecular biology and medicine.

Bacteriophage M13↗

PubMed2002

On the competition between water, sodium ions, and spermine in binding to DNA: a molecular dynamics computer simulation study.

The interaction of DNA with the polyamine spermine(4+) (Spm(4+)), sodium ions, and water molecules has been studied using molecular dynamics computer simulations in a system modeling a DNA crystal. The simulation model consisted of three B-DNA decamers in a periodic hexagonal cell, containing 1200 water molecules, 8 Spm(4+), 32 Na(+), and 4 Cl(-) ions. The present paper gives a more detailed account of a recently published report of this system and compares results on this mixed Spm(4+)/Na(+)-cation system with an molecular dynamics simulation carried out for the same DNA decamer under similar conditions with only sodium counterions (Korolev et al., J. Mol. Biol. 308:907). The presence of Spm(4+) makes significant influence on the DNA hydration and on the interaction of the sodium ions with DNA. Spermine pushes water molecules out of the minor groove, whereas Na(+) attracts and organizes water around DNA. The major binding site of the Spm(4+) amino groups and the Na(+) ions is the phosphate group of DNA. The flexible polyamine spermine displays a high presence in the minor groove but does not form long-lived and structurally defined complexes. Sodium ions compete with Spm(4+) for binding to the DNA bases in the minor groove. Sodium ions also have several strong binding sites in the major groove. The ability of water molecules, Spm(4+), and Na(+) to modulate the local structure of the DNA double helix is discussed.

Base Sequence↗

PubMed2002

Application of the Poisson Boltzmann polyelectrolyte model for analysis of equilibria between single-, double-, and triple-stranded polynucleotides in the presence of K(+), Na(+), and Mg(2+) ions.

The Poisson Boltzmann (PB) cell model of polyelectrolyte solution has been used for numerical calculations of the change in electrostatic free energy, DeltaG(el), for transformations between different structural forms (tri-, double-, and single-stranded) of the polyribonucleotides poly(rA).poly(rU)2, poly(rA).poly(rU), poly(rA), and poly(rU). In particular, the dependence on monovalent salt concentration, MCl (M = Na or K) in the absence and in the presence of MgCl(2) has been calculated. The results were obtained for conditions relevant to available experimental values of structural transition ("melting") temperatures (T(m)) and other thermodynamic quantities. Using the experimental T(m) values and theoretical electrostatic DeltaG(el), DeltaH(el), and DeltaS(el) functions, non-electrostatic contributions to the corresponding thermodynamic parameters of the poly(rA)/poly(rU) melting transitions were determined in MCl solutions in the absence of Mg(2+). Qualitative and to a large extent quantitative reproduction of the experimental calorimetry enthalpy, entropy and heat capacity values was found from the results of the PB theory. Furthermore, dependencies of T(m) on MCl concentration in the presence of MgCl(2) for the poly(rA)/poly(rU) transitions were also calculated. Compared to a model considering Mg(2+) as a fully-hydrated ion, much better agreement between experimental and PB theory was achieved by assuming the ion size of Mg(2+) to be given by that of a bare non-hydrated ion smaller than that of hydrated Na(+) or K(+). In agreement with data of experimental studies reported in literature, this result indicates that magnesium(II) can bind to RNA as a bare ion in a way that is different from that of DNA. Generally, we can conclude that the PB polyelectrolyte theory can provide an adequate description of thermally induced structural transitions in polydeoxy- and polyribonucleotides in different salt solutions in spite of the rather simplified model treating the solvent as dielectric continuum, the polyion as a uniformly charged cylinder, and the mobile ions as hard spheres in the absence of excluded volume effects.

DNA↗