Advanced simulation models to reveal genome structure in the cell nucleusMannheim 08 jun 2000 The use of supercomputers is indispensable to generate polymer chain models which allow to explore the three-dimensional structure of the genome and the dynamics of the cell nucleus. The Mannheim Supercomputer 2000 audience attentively listened to Dr. Joerg Langowski, head of the Division for Biophysics of Macromolecules at the Deutsches Krebsforschungszentrum in Heidelberg. Scientists from universities in Muenchen, Heidelberg and Grenoble, and the biophysical research institute in Prague teamed under the direction of Dr. Langowski to perform genome simulations on three different levels. As a result, the obtained models could be used to compute the distribution of chromosome territories in the cell nucleus and to compare the outcomes with experimental observations regarding the diffusion of fluorescent probes inside the nucleus.
The DNA in the living cell nucleus is a flexible macromolecule which is packaged on several levels, as Dr. Langowski explained. To generate a molecular dynamics simulation of DNA constitutes an enormous computational challenge, as well as the calculation of sequence-dependent DNA elasticity. The long-range protein-protein interaction is mediated by DNA. These long-range interactions are important for the regulation of gene activity. Often a gene is "switched on" by a protein which binds to a distant site on the genome. The DNA segments are connected through a harmonic binding and are bent into a circle.
The first level of genome packaging is the chromatin fiber where the DNA is wound around histone protein cores at regular intervals. The unit of two DNA windings round the histone core constitutes the nucleosome. The nucleosome chain has a diameter of 30 nanometer (nm). On a second level, the so-called solenoid model has been developed to arrange the nucleosomes in a regular helix. The linker DNA follows a continuous spiral path between the nucleosomes with a correspondingly large bend. Yet, an alternative model has been proposed, in which the linker DNA forms a straight path between the successive nucleosomes, according to the experimental data. Here, the regularity of the solenoid model is lost in favour of the zig-zag model.
At the highest level of compaction, the chromatin fiber is organised into chromosomes. During the metaphase in which the cell cycle amounts in cell division, the chromatin fiber is condensed into a clearly distinct entity or territory within the nucleus. Dr. Langowski explained how the intranuclear transport of macromolecules is happening in the space between these territories. Because today, we still lack the required computational strength to simulate the use of atom-scale molecular dynamics, the research team had to neglect the hydrodynamic and electrostatic features of the chromatin fiber. In turn, it is possible to make predictions about the mechanisms and time scales of intramolecular rearrangements.
The international team of Dr. Langowski applied Monte-Carlo and Brownian dynamics models to simulate the organisation of the chromatin fiber in a dynamic load balancing architecture. The scientists used the Metropolis algorithm to calculate and predict the influence of a bend on the structure of a superhelical DNA. A sequence-dependent or protein-induced bend is able to inhibit structural fluctuations in the superhelix and define the interactions between DNA segments which are separated by several hundreds of base pairs. The applied model harmonically corresponds to the different experimental parameters from dynamic light scattering, scanning force microscopy and neutron scattering.
The distribution of the chromatin fiber within a chromosome territory is far from random. The researchers used the Multi-Loop-Subcompartment (MLS) model to study the chromatin fiber folding into rosette-like loops. These rosettes are interconnected via a chromatin piece of similar base pair content, meaning that no protein matrix is required for structural support. The simulations of the Langowski team resulted in the formation of distinct chromosome territories. Contrarily to previous simulations, the MLS-model led to limited overlap between the chromosome territories, arms, and bends. It was found that the virtual confocal section of simulated nucleus shows interchromosomal domain channels.
Leslie Versweyveld |
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