From nucleosomes to chromatin fibers: molecular dynamics and Monte Carlo simulations of nucleosome organization and interactions

Chromosomes consist of a chain of nucleosomes, in which DNA wraps almost twice around a histone protein core. Nucleosomes are stable complexes and their position along the DNA regulates DNA accessibility. The underlying mechanisms of this process are still not understood well. In this thesis, molecular dynamics, steered molecular dynamics and Monte Carlo simulations were conducted to elucidate nucleosome organization and the folding of nucleosome chains into chromatin fibers at different length scales. The all-atom resolution of molecular dynamics simulations revealed a novel map of histone-DNA interaction sites extending experimental findings. By applying external forces the complete DNA unwrapping from the protein core at atomic resolution was investigated. This revealed intermediates of the pathway and an important contribution of the unstructured histone tails to nucleosome stability. Simulations of stretching coarse-grained chromatin fibers showed that experimental force-extension curves alone are insufficient to identify fiber geometry parameters and internucleosomal interaction strength. The chromatin fiber model was extended by a new description for DNA electrostatics to enable the translocation of nucleosomes within the fiber. The effect of this process on the stability of the fiber was strongly dependent on its geometry