Curves+, a revised version of the Curves software for analyzing the conformation of nucleic acid structures, is now available as a web server. This version, which can be freely accessed at http://gbio-pbil.ibcp.fr/cgi/Curves_plus/ , allows the user to upload a nucleic acid structure file, choose the nucleotides to be analyzed and after optionally setting a number of input variables, view the numerical and graphic results online or download files containing a set of helical, backbone and groove parameters that fully describe the structure. PDB format files are also provided for offline visualization of the helical axis and groove geometry.

We present the results of microsecond molecular dynamics simulations carried out by the ABC group of laboratories on a set of B-DNA oligomers containing the 136 distinct tetranucleotide base sequences. We demonstrate that the resulting trajectories have extensively sampled the conformational space accessible to B-DNA at room temperature. We confirm that base sequence effects depend strongly not only on the specific base pair step, but also on the specific base pairs that flank each step. Beyond sequence effects on average helical parameters and conformational fluctuations, we also identify tetranucleotide sequences that oscillate between several distinct conformational substates. By analyzing the conformation of the phosphodiester backbones, it is possible to understand for which sequences these substates will arise, and what impact they will have on specific helical parameters.

Microsecond molecular dynamics simulations of B-DNA oligomers carried out in an aqueous environment with a physiological salt concentration enable us to perform a detailed analysis of how potassium ions interact with the double helix. The oligomers studied contain all 136 distinct tetranucleotides and we are thus able to make a comprehensive analysis of base sequence effects. Using a recently developed curvilinear helicoidal coordinate method we are able to analyze the details of ion populations and densities within the major and minor grooves and in the space surrounding DNA. The results show higher ion populations than have typically been observed in earlier studies and sequence effects that go beyond the nature of individual base pairs or base pair steps. We also show that, in some special cases, ion distributions converge very slowly and, on a microsecond timescale, do not reflect the symmetry of the corresponding base sequence.

We present a new method for analyzing ion, or molecule, distributions around helical nucleic acids and illustrate the approach by analyzing data derived from molecular dynamics simulations. The analysis is based on the use of curvilinear helicoidal coordinates and leads to highly localized ion densities compared to those obtained by simply superposing molecular dynamics snapshots in Cartesian space. The results identify highly populated and sequence-dependent regions where ions strongly interact with the nucleic and are coupled to its conformational fluctuations. The data from this approach is presented as ion populations or ion densities (in units of molarity) and can be analyzed in radial, angular and longitudinal coordinates using 1D or 2D graphics. It is also possible to regenerate 3D densities in Cartesian space. This approach makes it easy to understand and compare ion distributions and also allows the calculation of average ion populations in any desired zone surrounding a nucleic acid without requiring references to its constituent atoms. The method is illustrated using microsecond molecular dynamics simulations for two different DNA oligomers in the presence of 0.15 M potassium chloride. We discuss the results in terms of convergence, sequence-specific ion binding and coupling with DNA conformation.

Uncovering the mechanisms that affect the binding specificity of transcription factors (TFs) is critical for understanding the principles of gene regulation. Although sequence-based models have been used successfully to predict TF binding specificities, we found that including DNA shape information in these models improved their accuracy and interpretability. Previously, we developed a method for modeling DNA binding specificities based on DNA shape features extracted from Monte Carlo (MC) simulations. Prediction accuracies of our models, however, have not yet been compared to accuracies of models incorporating DNA shape information extracted from X-ray crystallography (XRC) data or Molecular Dynamics (MD) simulations. Here, we integrated DNA shape information extracted from MC or MD simulations and XRC data into predictive models of TF binding and compared their performance. Models that incorporated structural information consistently showed improved performance over sequence-based models regardless of data source. Furthermore, we derived and validated nine additional DNA shape features beyond our original set of four features. The expanded repertoire of 13 distinct DNA shape features, including six intra-base pair and six inter-base pair parameters and minor groove width, is available in our R/Bioconductor package DNAshapeR and enables a comprehensive structural description of the double helix on a genome-wide scale.