Theoretical study of large conformational transitions in DNA: the B↔A conformational change in water and ethanol/water

We explore here the possibility of determining theoretically the free energy change associated with large conformational transitions in DNA, like the solvent-induced B⇔A conformational change. We find that a combination of targeted molecular dynamics (tMD) and the weighted histogram analysis method (WHAM) can be used to trace this transition in both water and ethanol/water mixture. The pathway of the transition in the A→B direction mirrors the B→A pathway, and is dominated by two processes that occur somewhat independently: local changes in sugar puckering and global rearrangements (particularly twist and roll) in the structure. The B→A transition is found to be a quasi-harmonic process, which follows closely the first spontaneous deformation mode of B-DNA, showing that a physiologically-relevant deformation is in coded in the flexibility pattern of DNA

A measure of bending in nucleic acids structures applied to A-tract DNA

A method is proposed to measure global bending in DNA and RNA structures. It relies on a properly defined averaging of base-fixed coordinate frames, computes mean frames of suitably chosen groups of bases and uses these mean frames to evaluate bending. The method is applied to DNA A-tracts, known to induce considerable bend to the double helix. We performed atomistic molecular dynamics simulations of sequences containing the A4T4 and T4A4 tracts, in a single copy and in two copies phased with the helical repeat. Various temperature and salt conditions were investigated. Our simulations indicate bending by roughly 10° per A4T4 tract into the minor groove, and an essentially straight structure containing T4A4, in agreement with electrophoretic mobility data. In contrast, we show that the published NMR structures of analogous sequences containing A4T4 and T4A4 tracts are significantly bent into the minor groove for both sequences, although bending is less pronounced for the T4A4 containing sequence. The bending magnitudes obtained by frame averaging are confirmed by the analysis of superhelices composed of repeated tract monomers

A two-step target binding and selectivity support vector machines approach for virtual screening of dopamine receptor subtype-selective ligands

10.1371/journal.pone.0039076PLoS ONE76

Action at a distance in supercoiled DNA: effects of sequence on slither, branching, and intramolecular concentration.

We report a computer modeling study of DNA supercoiling in model plasmids over the size range of 140-1260 bp. We used a computer model with basepair resolution. Molecular dynamics was used to produce ensembles at 300 K and to investigate intramolecular motions. The plasmid models varied by their sequence. The sequence types employed for comparison included a curve-bearing plasmid, a heterogenous sequence plasmid, and a homogenous sequence. Within the three sequence types tested at the 1260-bp plasmid size, we observed several sequence-dependent phenomena. Writhe, radius of gyration, slither motion, and branching probability were seen to be sequence dependent. Branching probability was the least in the homogenous plasmid and the greatest in the curve-bearing plasmid. The curve imposed a symmetry on the plasmid that was absent in the heterogenous sequence. Significant localizations and enhancements of intramolecular concentration were seen to a persistence length. Molecular dynamics allowed us to observe the mechanism of branch formation and reabsorption. We observed a size-dependent change in the types of motion observed in plasmids. Slither motion predominated in plasmids up to 600 bp in size, whereas global rearrangements were more important in the 1260 mer

Dehydrating agents sharply reduce curvature in DNAs containing A tracts.

The structural basis of DNA curvature remains elusive, because models for curvature based on crystallographic structures of molecules containing A tracts do not agree with any of the models for sequence-directed curvature based on solution studies. Here we demonstrate that the difference is probably due to MPD (2-methyl-2,4-pentanediol), the dehydrating agent commonly used in crystallography. One characteristic signature of curved DNA molecules is that they run anomalously slowly on polyacrylamide gels, appearing to be larger than they actually are. The gel anomalies of three curved DNAs from trypanosome kinetoplast minicircles drop monotonically with increasing MPD concentration, indicating that MPD straightens molecules that are curved in aqueous solution. This is not due to some non-specific effect of MPD on poly(dA) or polypurine tracts, because control molecules containing dA70 and dG43 run normally over the full range of MPD concentrations. Circular dichroism spectra are not affected by MPD, ruling out a conformational change to a structure outside the B-DNA family. The effect is not due to MPD-induced changes in phasing of the curved sequences, because MPD has virtually no effect on the linking numbers of relaxed plasmids containing either curved sequences or dA70. At the concentrations of MPD used in X-ray crystallography, the curvature of DNAs containing A tracts is substantially lower than in solution, which probably explains the ongoing discrepancies between the crystallographic results and models based on solution studies