To approach the three-dimensional organization of the human cell nucleus, the structural-, scaling- and dynamic
properties of interphase chromosomes and cell nuclei were simulated with Monte Carlo and Brownian Dynamics
methods. The 30 nm chromatin fibre was folded according to the Multi-Loop-Subcompartment (MLS) model, in
which ~100 kbp loops form rosettes, connected by a linker, and the Random-Walk/Giant-Loop (RW/GL)
topology, in which 1-5 Mbp loops are attached to a flexible backbone. Both the MLS and the RW/GL model
form chromosome territories but only the MLS rosettes result in distinct subcompartments visible with light
microscopy and low overlap of chromosomes, -arms and subcompartments. This morphology and the size of
subcompartments agree with the morphology found by expression of histone auto-fluorescent protein fusions
and fluorescence in situ hybridization (FISH) experiments. Even small changes of the model parameters induced
significant rearrangements of the chromatin morphology. Thus, pathological diagnoses based on this
morphology, are closely related to structural changes on the chromatin level. The position of interphase
chromosomes depends on their metaphase location, and suggests a possible origin of current experimental
findings. The chromatin density distribution of simulated confocal (CLSM) images agrees with the MLS model
and with recent experiments. The scaling behaviour of the chromatin fiber topology and morphology of CLSM
stacks revealed fine-structured multi-scaling behaviour in agreement with the model prediction. Review and
comparison of experimental to simulated spatial distance measurements between genomic markers as function of
their genomic separation also favour an MLS model with loop and linker sizes of 63 to 126 kbp. Visual
inspection of the morphology reveals also big spaces allowing high accessibility to nearly every spatial location,
due to the chromatin occupancy <30% and a mean mesh spacing of 29 to 82 nm for nuclei of 6 to 12 μm
diameter. The simulation of diffusion agreed with this structural prediction, since the mean displacement for 10
nm sized particles of ~1 to 2 μm takes place within 10 ms. Therefore, the diffusion of biological relevant tracers
is only moderately obstructed, with the degree of obstruction ranging from 2.0 to 4.0 again in experimental
agreement
