Biophysical Society Thematic Meeting| Les Houches 2019

Multiscale Modeling of Chromatin: Bridging Experiment with Theory

Monday Speaker Abstracts

FROM DNA TO CHROMATIN: MULTISCALE MODELS FROM ATOMISTIC TO KB LEVEL Jürgen Walther 1 ; Pablo Dans 1 ; Modesto Orozco 1 ; 1 IRB Barcelona, Barcelona, Barcelona, Spain The three dimensional organization of chromatin inside the cell nucleus is expected to strongly depend on sequence specific properties of nucleosomal and linker DNA. However, recent experiments cannot capture yet the characteristics of chromatin arrangement on the resolution level of a single base-pair. To model the chromatin fiber with bp-level accuracy we developed a coarse-grained DNA model (MCDNA). MCDNA is available as a web tool (http://mmb.irbbarcelona.org/MCDNA/) for the three-dimensional simulation of free DNA and medium-sized chromatin fibers. The program implements a novel Monte Carlo algorithm based on a mesoscopic model, using a tetramer-dependent base-pair step model fitted to reproduce parmbsc1 atomistic molecular dynamics (MD) simulations. By projecting the Monte Carlo ensembles to the atomistics level the model accurately reproduces base-pair geometries, groove widths and backbone conformations compared to atomistic MD. The method provides ensembles of quality comparable to those obtained from atomistic MD, but at a tiny fraction of the computational cost, allowing to study systems much larger than those explored by atomistic MD. MCDNA is extended to a chromatin fiber model (Chromatin Dynamics). Chromatin Dynamics keeps the bp-step accuracy of MCDNA but is also able to simulate kb long fibers. Chromatin Dynamics is used for several applications, for example for modeling Micro-C/ high resolution Hi-C data, for visualizing oligo- and immuno-STORM microscopy images or for investigating the existence of an evolutionary-driven preferred chromatin fiber configuration.

THE MECHANICAL GENOME Helmut Schiessel 1 ; 1 Leiden University, Lorentz Institute, Leiden, Zuid-Holland, The Netherlands

This talk focuses on a second layer of information in DNA molecules, namely on sequence- dependent DNA mechanics that guides DNA packaging inside cells. We use a mutation Monte Carlo technique on a coarse-grained nucleosome model to calculate the sequence preferences of nucleosomes and to demonstrate the possibility of multiplexing mechanical and classical genetic information. This allows to guide on top of genes the packaging of DNA into nucleosomes with single base-pair precision. We demonstrate this explicitly for the genome of baker’s yeast by mapping nucleosomal DNA sequences on weighted graphs. We then focus on transcription start sites of various organisms and find a simple general rule: on average, nucleosomes are intrinsically repelled from transcription start sites for unicellular life but the opposite holds true for multicellular life. We speculate about a possible biological reason behind this difference.

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