(J-362) The Impact of Charge regulation and the Ionic Intranuclear Environment on Chromatin charge and Structure

Introduction::It remains an open question how chromatin is structured inside the nucleus while mitigating the electrostatic repulsions induced by the charged system. The intranuclear environment, including ions, pH, and crowder density, which includes chromatin density, are expected to regulate chromatin structure and charge. Previous experiments have demonstrated that the electrolyte environment influences DNA and chromatin structure, ranging from local properties, such as persistence length, to compaction of chromatin domains, and even cell fate. However, experiments are unable to concomitantly measure all relevant properties of the system to definitively identify the principal mechanisms of charging and packing. On the other hand, numerous computational approaches, ranging from all-atomistic to coarse-grained simulations, have helped to mechanistically uncover the effects of ions on chromatin. However, atomistic or MD simulations are impractical to conduct a systematic investigation into the effect of varying ionic environments, crowding density, and pH-dependent charge regulation on chromatin structure, owing to the significant computational expense incurred by accurate dynamic representation of these effects. Therefore, most computations molecular simulations are often performed for fixed system charges and fixed pH and employ a coarse-grained representation of chromatin.

Materials and Methods:: Here, we introduce a detailed statistical mechanics model known as Molecular Theory (MT) to investigate how the intranuclear environment influences the structure and charge. MT explicitly considers the size, shape, conformations, charges, and chemical states of all molecular species, thus linking the structural state with the chemical or charged state of the system. Importantly, using MT, it is computationally feasible to cover a wide range of environmental conditions. Here, we use a molecular theoretical approach to determine how the packing and charge of small nucleosome arrays (1-mer and 8-mer) change in response to varied environmental conditions.

Results, Conclusions, and Discussions::

We determined that the effective charge of the nucleosome array depends on salt concentration, pH, nucleosome concentration, and structural quantities such as nucleosome spacing and size, and bond angle. We presume that these interactions have major significance in the 3D chromatin organization of chromatin as it provides principles the structure must heed in order to mitigate the abundance of charges in the system. 

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