An integrated 3-Dimensional Genome Modeling Engine for data-driven simulation of spatial genome organization.

ChIA-PET is a high-throughput mapping technology that reveals long-range chromatin interactions and provides insights into the basic principles of spatial genome organization and gene regulation mediated by specific protein factors. Recently, we showed that a single ChIA-PET experiment provides information at all genomic scales of interest, from the high-resolution locations of binding sites and enriched chromatin interactions mediated by specific protein factors, to the low resolution of nonenriched interactions that reflect topological neighborhoods of higher-order chromosome folding. This multilevel nature of ChIA-PET data offers an opportunity to use multiscale 3D models to study structural-functional relationships at multiple length scales, but doing so requires a structural modeling platform. Here, we report the development of 3D-GNOME (3-Dimensional Genome Modeling Engine), a complete computational pipeline for 3D simulation using ChIA-PET data. 3D-GNOME consists of three integrated components: a graph-distance-based heat map normalization tool, a 3D modeling platform, and an interactive 3D visualization tool. Using ChIA-PET and Hi-C data derived from human B-lymphocytes, we demonstrate the effectiveness of 3D-GNOME in building 3D genome models at multiple levels, including the entire genome, individual chromosomes, and specific segments at megabase (Mb) and kilobase (kb) resolutions of single average and ensemble structures. Further incorporation of CTCF-motif orientation and high-resolution looping patterns in 3D simulation provided additional reliability of potential biologically plausible topological structures.

GDFuzz3D: a method for protein 3D structure reconstruction from contact maps, based on a non-Euclidean distance function.

MOTIVATION: To date, only a few distinct successful approaches have been introduced to reconstruct a protein 3D structure from a map of contacts between its amino acid residues (a 2D contact map). Current algorithms can infer structures from information-rich contact maps that contain a limited fraction of erroneous predictions. However, it is difficult to reconstruct 3D structures from predicted contact maps that usually contain a high fraction of false contacts. RESULTS: We describe a new, multi-step protocol that predicts protein 3D structures from the predicted contact maps. The method is based on a novel distance function acting on a fuzzy residue proximity graph, which predicts a 2D distance map from a 2D predicted contact map. The application of a Multi-Dimensional Scaling algorithm transforms that predicted 2D distance map into a coarse 3D model, which is further refined by typical modeling programs into an all-atom representation. We tested our approach on contact maps predicted de novo by MULTICOM, the top contact map predictor according to CASP10. We show that our method outperforms FT-COMAR, the state-of-the-art method for 3D structure reconstruction from 2D maps. For all predicted 2D contact maps of relatively low sensitivity (60-84%), GDFuzz3D generates more accurate 3D models, with the average improvement of 4.87 Å in terms of RMSD. AVAILABILITY AND IMPLEMENTATION: GDFuzz3D server and standalone version are freely available at http://iimcb.genesilico.pl/gdserver/GDFuzz3D/. CONTACT: iamb@genesilico.pl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RNAmap2D - calculation, visualization and analysis of contact and distance maps for RNA and protein-RNA complex structures.

BACKGROUND: The structures of biological macromolecules provide a framework for studying their biological functions. Three-dimensional structures of proteins, nucleic acids, or their complexes, are difficult to visualize in detail on flat surfaces, and algorithms for their spatial superposition and comparison are computationally costly. Molecular structures, however, can be represented as 2D maps of interactions between the individual residues, which are easier to visualize and compare, and which can be reconverted to 3D structures with reasonable precision. There are many visualization tools for maps of protein structures, but few for nucleic acids. RESULTS: We developed RNAmap2D, a platform-independent software tool for calculation, visualization and analysis of contact and distance maps for nucleic acid molecules and their complexes with proteins or ligands. The program addresses the problem of paucity of bioinformatics tools dedicated to analyzing RNA 2D maps, given the growing number of experimentally solved RNA structures in the Protein Data Bank (PDB) repository, as well as the growing number of tools for RNA 2D and 3D structure prediction. RNAmap2D allows for calculation and analysis of contacts and distances between various classes of atoms in nucleic acid, protein, and small ligand molecules. It also discriminates between different types of base pairing and stacking. CONCLUSIONS: RNAmap2D is an easy to use method to visualize, analyze and compare structures of nucleic acid molecules and their complexes with other molecules, such as proteins or ligands and metal ions. Its special features make it a very useful tool for analysis of tertiary structures of RNAs. RNAmap2D for Windows/Linux/MacOSX is freely available for academic users at http://iimcb.genesilico.pl/rnamap2d.html.

PROTMAP2D: visualization, comparison and analysis of 2D maps of protein structure.

MOTIVATION: Protein structure comparison is a fundamental problem in structural biology and bioinformatics. Two-dimensional maps of distances between residues in the structure contain sufficient information to restore the 3D representation, while maps of contacts reveal characteristic patterns of interactions between secondary and super-secondary structures and are very attractive for visual analysis. The overlap of 2D maps of two structures can be easily calculated, providing a sensitive measure of protein structure similarity. PROTMAP2D is a software tool for calculation of contact and distance maps based on user-defined criteria, quantitative comparison of pairs or series of contact maps (e.g. alternative models of the same protein, model versus native structure, different trajectories from molecular dynamics simulations, etc.) and visualization of the results. AVAILABILITY: PROTMAP2D for Windows / Linux / MacOSX is freely available for academic users from http://genesilico.pl/protmap2d.htm