CURVES+ web server for analyzing and visualizing the helical, backbone and groove parameters of nucleic acid structures

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

BIGNASim: A NoSQL database structure and analysis portal for nucleic acids simulation data

Molecular dynamics simulation (MD) is, just behind genomics, the bioinformatics tool that generates the largest amounts of data, and that is using the largest amount of CPU time in supercomputing centres. MD trajectories are obtained after months of calculations, analysed in situ, and in practice forgotten. Several projects to generate stable trajectory databases have been developed for proteins, but no equivalence exists in the nucleic acids world. We present here a novel database system to store MD trajectories and analyses of nucleic acids. The initial data set available consists mainly of the benchmark of the new molecular dynamics force-field, parmBSC1. It contains 156 simulations, with over 120s of total simulation time. A deposition protocol is available to accept the submission of new trajectory data. The database is based on the combination of two NoSQL engines, Cassandra for storing trajectories and MongoDB to store analysis results and simulation metadata. The analyses available include backbone geometries, helical analysis, NMR observables and a variety of mechanical analyses. Individual trajectories and combined metatrajectories can be downloaded from the portal. The system is accessible through http://mmb.irbbarcelona.org/BIGNASim/. Supplementary Material is also available on-line at http://mmb.irbbarcelona.org/BIGNASim/SuppMaterial/

MOLECULAR DYNAMICS STUDY OF NON-HYDROGEN-BONDING BASE-PAIR DNA DUPLEX d(GTCDNAM GCGCCGTGGC). d(GCCACGGCGCD5SICSGAC)

Objective: The objective of the study was to elucidate the structural activity of a natural DNA sequence modified by a hydrophobic base-pair which didn't form Watson-Crick (W-C) hydrogen-bond. The modified unnatural base-pair (DNAM-D5SICS) was introduced in DNA sequences of 14-mer for molecular dynamics study in water solution.Methods: A 200 ns molecular-dynamics-simulation in orthogonal-box-water-solvent, using Particle-mesh-Ewald-method (PME) within periodic-boundary-condition (PBC) was performed by using AMBER-14 code. The force-field-ff12SB-force-field was used during the simulation while the force-field-parameters of modified base-pair, compatible to ff12SB-force-field, were calculated by Gaussian-09-code using ab-inito/Hartree-Fock-methodology. The code CPPTRAJ, (a module of AMBER-14) CURVE and Chimera were used in the analysis of the data.Results: Root mean square deviation (RMSD) of heavy atoms of the trajectory revealed that the structure of the equilibrated duplex was stable, sequence-dependent and had mixed DNA-conformation. A little distortion near to the neighbor of the modified base-pair in the duplex strand was observed. However, we got a stabilized structure of such type of duplex if we placed modified base-pair after the third place in the strand.Conclusion: The study concluded that the distortion produced by modified-base-pair in the overall structure of duplex was local while the confirmation of such type of duplex was mixed and maintained the Watson-Crick (W-C) integrity of DNA. The study would help in the use of hydrophobic base-pair materials in biotechnological applications and the understanding of their structure-function relationship

do_x3dna: A tool to analyze structural fluctuations of dsDNA or dsRNA from molecular dynamics simulations.

The do_x3dna package has been developed to analyze the structural fluctuations of DNA or RNA during molecular dynamics simulations. It extends the capability of the 3DNA package to GROMACS MD trajectories and includes new methods to calculate the global-helical axis of DNA and bending fluctuations during simulations. The package also includes a Python module dnaMD to perform and visualize statistical analyses of complex data obtained from the trajectories

5-Formylcytosine alters the structure of the DNA double helix.

The modified base 5-formylcytosine (5fC) was recently identified in mammalian DNA and might be considered to be the 'seventh' base of the genome. This nucleotide has been implicated in active demethylation mediated by the base excision repair enzyme thymine DNA glycosylase. Genomics and proteomics studies have suggested an additional role for 5fC in transcription regulation through chromatin remodeling. Here we propose that 5fC might affect these processes through its effect on DNA conformation. Biophysical and structural analysis revealed that 5fC alters the structure of the DNA double helix and leads to a conformation unique among known DNA structures including those comprising other cytosine modifications. The 1.4-Å-resolution X-ray crystal structure of a DNA dodecamer comprising three 5fCpG sites shows how 5fC changes the geometry of the grooves and base pairs associated with the modified base, leading to helical underwinding.E.-A.R. is supported as a Herchel Smith Fellow. The Balasubramanian laboratory is supported by a Senior Investigator Award from the Wellcome Trust (099232/Z/12/Z to S.B.), and it also receives core funding from Cancer Research UK (C9681/A11961 to S.B.). D.Y.C. is supported by the Crystallographic X-ray Facility (CXF) at the Department of Biochemistry, University of Cambridge, and B.F.L. is supported by the Wellcome Trust (076846/Z/05/A to B.F.L.). We thank the staff of Soleil and Diamond Light Source for use of facilities. We thank C. Calladine for stimulating discussions.This is the accepted manuscript for a paper published in Nature Structural & Molecular Biology 22, 44–49 (2015) doi: 10.1038/nsmb.293

BIGNASim: a NoSQL database structure and analysis portal for nucleic acids simulation data.

Molecular dynamics simulation (MD) is, just behind genomics, the bioinformatics tool that generates the largest amounts of data, and that is using the largest amount of CPU time in supercomputing centres. MD trajectories are obtained after months of calculations, analysed in situ, and in practice forgotten. Several projects to generate stable trajectory databases have been developed for proteins, but no equivalence exists in the nucleic acids world. We present here a novel database system to store MD trajectories and analyses of nucleic acids. The initial data set available consists mainly of the benchmark of the new molecular dynamics force-field, parmBSC1. It contains 156 simulations, with over 120 of total simulation time. A deposition protocol is available to accept the submission of new trajectory data. The database is based on the combination of two NoSQL engines, Cassandra for storing trajectories and MongoDB to store analysis results and simulation metadata. The analyses available include backbone geometries, helical analysis, NMR observables and a variety of mechanical analyses. Individual trajectories and combined meta-trajectories can be downloaded from the portal. The system is accessible through http: //mmb.irbbarcelona.org/BIGNASim/. Supplementary Material is also available on-line at http://mmb. irbbarcelona.org/BIGNASim/SuppMaterial/.Spanish Ministry of Science [BIO2012-32868, SEV-2011-00067, TIN2012-34557]; Catalan Government [2014-SGR-134, 2014-SGR-1051]; Institut Català de Recerca I Estudis Avanc¸ats, ICREA Academia [to M.O.], Instituto de Salud Carlos III-Instituto Nacional de Bioinformática [PT13/0001/0019, PT13/0001/0028]; European Research Council [ERC SimDNA]; European Union, H2020 programme [Elixir-Excellerate: 676559; BioExcel: 674728, MuG: 676566]; PEDECIBA and SNI (ANII, Uruguay) [to P.D.D.]. Funding for open access charge: European Union [MuG: 676566].Peer ReviewedPostprint (published version

Analyzing ion distributions around DNA

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 conformatio

Analyzing ion distributions around DNA: sequence-dependence of potassium ion distributions from microsecond molecular dynamics

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 sequenc

Analyzing ion distributions around DNA

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

Geometric modeling, simulation, and visualization methods for plasmid DNA molecules

Plasmid DNA molecules are a special type of DNA molecules that are used, among other applications, in DNA vaccination and gene therapy. These molecules are characterized by, when in their natural state, presenting a closed-circular conformation and by being supercoiled. The production of plasmid DNA using bacteria as hosts implies a purification step where the plasmid DNA molecules are separated from the DNA of the host and other contaminants. This purification process, and all the physical and chemical variations involved, such as temperature changes, may affect the plasmid DNA molecules conformation by uncoiling or even by open them, which makes them useless for therapeutic applications. Because of that, researchers are always searching for new purification techniques that maximize the amount of supercoiled plasmid DNA that is produced. Computer simulations and 3D visualization of plasmid DNA can bring many advantages because they allow researchers to actually see what can happen to the molecules under certain conditions. In this sense, it was necessary to develop reliable and accurate geometric models specific for plasmid DNA simulations. This dissertation presents a new assembling algorithm for B-DNA specifically developed for plasmid DNA assembling. This new assembling algorithm is completely adaptive in the sense that it allows researchers to assemble any plasmid DNA base-pair sequence along any arbitrary conformation that fits the length of the plasmid DNA molecule. This is specially suitable for plasmid DNA simulations, where conformations are generated by simulation procedures and there is the need to assemble the given base-pair sequence over that conformation, what can not be done by conventional predictive DNA assembling methods. Unlike traditional molecular visualization methods that are based on the atomic structure, this new assembling algorithm uses color coded 3D molecular surfaces of the nucleotides as the building blocks for DNA assembling. This new approach, not only reduces the amount of graphical objects and, consequently, makes the rendering faster, but also makes it easier to visually identify the nucleotides in the DNA strands. The algorithm used to triangulate the molecular surfaces of the nucleotides building blocks is also a novelty presented as part of this dissertation. This new triangulation algorithm for Gaussian molecular surfaces introduces a new mechanism that divides the atomic structure of molecules into boxes and spheres. This new space division method is faster because it confines the local calculation of the molecular surface to a specific region of influence of the atomic structure, not taking into account atoms that do not influence the triangulation of the molecular surface in that region. This new method also guarantees the continuity of the molecular surface. Having in mind that the aim of this dissertation is to present a complete set of methods for plasmid DNA visualization and simulation, it is also proposed a new deformation algorithm to be used for plasmid DNA Monte Carlo simulations. This new deformation algorithm uses a 3D polyline to represent the plasmid DNA conformation and performs small deformations on that polyline, keeping the segments length and connectivity. Experiments have been performed in order to compare this new deformation method with deformation methods traditionally used by Monte Carlo plasmid DNA simulations These experiments shown that the new method is more efficient in the sense that its trial acceptance ratio is higher and it converges sooner and faster to the elastic energy equilibrium state of the plasmid DNA molecule. In sum, this dissertation successfully presents an end-to-end set of models and algorithms for plasmid DNA geometric modelling, visualization and simulation