Spring Model – chromatin modeling tool based on OpenMM

Chromatin structures modelling is a rapidly developing field. Parallel to the enormous growth of available experimental data, there is a growing need of building and visualizing 3D structures of nuclei, chromosomes, chromatin domains, and single loops associated with particular genes locus. Here we present a tool for chromatin domain modeling. It is available as a webserver and standalone python script. Our tool is based on molecular mechanics. It uses OpenMM engine for building models. In this method, the user has to provide contacts and will obtain 3D structure that satisfies these contacts. Additional extra parameters allow controlling fibre stiffness, type of initial structure, resolution. There are also options for structure refinement, and modelling in a spherical container. A user may provide contacts using beads indices, or paste interactions in genome coordinates from BEDPE file. After modelling user is able to download the structure in Protein Data Bank (PDB) file format for further analysis. We dedicate this tool for all who are interested in chromatin structures. It is suitable for quick visualization of datasets, studying the impact of structural variants (SVs), inspecting the effects of adding and removing particular contacts, measuring features like maximum distances between certain sites (e.g. promotor-enhancer) or local density of chromatin.

[1]  P ? ? ? ? ? ? ? % ? ? ? ? , 1991 .

[2]  A. Lesne,et al.  3D genome reconstruction from chromosomal contacts , 2014, Nature Methods.

[3]  Rodolfo Ghirlando,et al.  CTCF: making the right connections , 2016, Genes & development.

[4]  Neva C. Durand,et al.  Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes , 2015, Proceedings of the National Academy of Sciences.

[5]  P. Wolynes,et al.  Topology, structures, and energy landscapes of human chromosomes , 2015, Proceedings of the National Academy of Sciences.

[6]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[7]  Stefan Friedrich,et al.  Topology , 2019, Arch. Formal Proofs.

[8]  Mario Nicodemi,et al.  Complexity of chromatin folding is captured by the strings and binders switch model , 2012, Proceedings of the National Academy of Sciences.

[9]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[10]  Daniel S. Day,et al.  Activation of proto-oncogenes by disruption of chromosome neighborhoods , 2015, Science.

[11]  Shaun Mahony,et al.  miniMDS: 3D structural inference from high-resolution Hi-C data , 2017, bioRxiv.

[12]  Dariusz Plewczynski,et al.  Free energy based high-resolution modeling of CTCF-mediated chromatin loops for human genome , 2017, bioRxiv.

[13]  Dariusz Plewczynski,et al.  3D-GNOME: an integrated web service for structural modeling of the 3D genome , 2016, Nucleic Acids Res..

[14]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[15]  Melike Lakadamyali,et al.  Advanced microscopy methods for visualizing chromatin structure , 2015, FEBS letters.

[16]  L. Mirny.  The fractal globule as a model of chromatin architecture in the cell , 2011, Chromosome Research.

[17]  Dariusz Plewczynski,et al.  One protein to rule them all: The role of CCCTC-binding factor in shaping human genome in health and disease. , 2019, Seminars in cell & developmental biology.

[18]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[19]  Dariusz M Plewczynski,et al.  CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription , 2015, Cell.

[20]  William Stafford Noble,et al.  Massively multiplex single-cell Hi-C , 2016, Nature Methods.

[21]  A. Tanay,et al.  Single cell Hi-C reveals cell-to-cell variability in chromosome structure , 2013, Nature.

[22]  J. Dekker,et al.  Hi-C: a comprehensive technique to capture the conformation of genomes. , 2012, Methods.

[23]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[24]  Sébastien Phan,et al.  ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells , 2017, Science.

[25]  Shlomo Havlin,et al.  Crumpled globule model of the three-dimensional structure of DNA , 1993 .

[26]  Danna Zhou,et al.  d. , 1934, Microbial pathogenesis.

[27]  Tsuyoshi Murata,et al.  {m , 1934, ACML.

[28]  Dariusz Plewczynski,et al.  Machine learning polymer models of three-dimensional chromatin organization in human lymphoblastoid cells. , 2019, Methods.

[29]  Noam Kaplan,et al.  The Hitchhiker's guide to Hi-C analysis: practical guidelines. , 2015, Methods.

[30]  William Stafford Noble,et al.  Integrative annotation of chromatin elements from ENCODE data , 2012, Nucleic acids research.

[31]  Diwakar Shukla,et al.  OpenMM 4: A Reusable, Extensible, Hardware Independent Library for High Performance Molecular Simulation. , 2013, Journal of chemical theory and computation.