Development of a multiscale coarse-grained chromatin model

Abstract

An important challenge in understanding gene behavior is deciphering how the genome is organized in space and how this organization influences its function. Existing experimental and computational methods lack the ability to provide close up views of the structure of biomolecules inside nano-scale chromatin. In this thesis, we develop a multiscale coarse-grained chromatin model, which integrates all-atom representations of proteins, DNA, and nucleosomes; a chemically specific coarse-grained model of kb scale chromatin; and a minimal model of sub-Mb scale chromatin. A key feature of this model is its capacity to link the molecular details of nucleosomes to the collective behavior of mesoscale (up to sub-Mb scale) chromatin. Our chemically-specific model describes DNA at base-pair resolution and proteins at amino-acid level resolution. We have used this model to investigate how sub-nucleosome level physicochemical and structural properties, such as the spontaneous thermal breathing and sliding motion of DNA, affect larger scale chromatin self-assembly. Nucleosome breathing refers to the observation that nucleosomes, rather than being static particles, exhibit spontaneous structural fluctuations where the DNA binds and unbinds dynamically. We find that such plasticity of nucleosomes destabilizes the highly regular zig-zag fiber chromatin folding configurations, and promotes instead an irregular and dynamical organization of nucleosomes termed `liquid-like'. Our model can also be used to investigate the effects of DNA sequence, salt conditions, and binding of additional proteins on the behavior of chromatin. Our minimal model describes nucleosomes with just a few particles, while still explicitly representing the DNA. We have used our minimal model to investigate the phase behavior of systems of multiple interacting chromatin fibers. We find that chromatin undergoes salt-mediated liquid-liquid phase separation, and that nucleosome plasticity plays an important role in increasing the range of stability of the coexistence region. Additionally, the model is able to investigate the size scaling properties of chromatin fibers and the effect of nucleosome repeat length on chromatin compaction and inter-chromatin interactions. Together, our multiscale methodology provides a useful technique to extrapolate atomistic properties of nucleosomes to the modulation of large-scale chromatin organization.