An Advanced Coarse-Grained Nucleosome Core Particle Model for Computer Simulations of Nucleosome-Nucleosome Interactions under Varying Ionic Conditions

Abstract

In the eukaryotic cell nucleus, DNA exists as chromatin, a compact but dynamic complex with histone proteins. The first level of DNA organization is the linear array of nucleosome core particles (NCPs). The NCP is a well-defined complex of 147 bp DNA with an octamer of histones. Interactions between NCPs are of paramount importance for higher levels of chromatin compaction. The polyelectrolyte nature of the NCP implies that nucleosome-nucleosome interactions must exhibit a great influence from both the ionic environment as well as the positively charged and highly flexible N-terminal histone tails, protruding out from the NCP. The large size of the system precludes a modelling analysis of chromatin at an all-atom level and calls for coarse-grained approximations. Here, a model of the NCP that include the globular histone core and the flexible histone tails described by one particle per each amino acid and taking into account their net charge is proposed. DNA wrapped around the histone core was approximated at the level of two base pairs represented by one bead (bases and sugar) plus four beads of charged phosphate groups. Computer simulations, using a Langevin thermostat, in a dielectric continuum with explicit monovalent (K+), divalent (Mg2+) or trivalent (Co(NH3)6 3+) cations were performed for systems with one or ten NCPs. Increase of the counterion charge results in a switch from repulsive NCP-NCP interaction in the presence of K+, to partial aggregation with Mg2+ and to strong mutual attraction of all 10 NCPs in the presence of CoHex3+. The new model reproduced experimental results and the structure of the NCP-NCP contacts is in agreement with available data. Cation screening, ion-ion correlations and tail bridging contribute to the NCP-NCP attraction and the new NCP model accounts for these interactions.

The energy components of stacked chromatin layers explain the morphology, dimensions and mechanical properties of metaphase chromosomes

“…This introduces covalent cross-links into the structure in addition to the electrostatic interactions responsible for histone -DNA and nucleosome-nucleosome associations [74][75][76]. Therefore, as in the case of other soft-matter structures [77], it is better to consider that chromosomes are hydrogels with a liquid crystal organization.…”

A Coarse-Grained DNA Model Parameterized from Atomistic Simulations by Inverse Monte Carlo

“…An advanced coarse-grained DNA model was recently introduced by us [56] in order to model DNA in nucleosome complexes. It consists of two types of sites: DNA core ("D") beads, each representing two base pairs and "P" beads, representing phosphate groups.…”

“…In the present work we parameterize the coarse-grained DNA model introduced in [56] (Figure 1A,B) with the aim to reproduce the experimental salt dependence of DNA flexibility. The parameterization is based on atomistic simulations of DNA oligomers in water solution with K + as counterions.…”

Multiscale simulation of DNA

“…Early in vitro experiments [155] suggested the compaction of the nucleosome string into a 30 nm fiber, but the situation in vivois probably more complex ( Figure 1) and depends on many variables such as the linker length, ionic environment, the presence/absence of linker histones and the effect of chromatin remodelers [156,157].…”

“…We can divide computational approaches of chromatin structure into three basic [156,160], ionic environment [157,161], presence of linker histones [163] and different intra-and inter-chain physical interactions [156,157,[160][161][162][163][164]. In the top-down models the chromatin structure is derived by implementing experimental restraints coming from chromosome conformation capture techniques into a simple model of the chromatin fiber.…”